Metabolic Signaling in the Tumor Microenvironment
Simple Summary
Abstract
1. Introduction
2. Oncogenic Cell Signaling Drives Metabolic Reprogramming
2.1. MYC
2.2. HIF
2.3. Akt and mTOR
2.4. AMPK
2.5. RAS and EGFR
3. Metabolites Play Crucial Roles in Intratumoral Signaling
3.1. Glucose and Lactate
3.1.1. Cancer Cells
3.1.2. T and NK Cells
3.1.3. Treg Cells
3.1.4. Tumor-Associated Macrophages
3.1.5. Cancer-Associated Fibroblasts
3.1.6. Dendritic Cells
3.1.7. Myeloid-Derived Suppressor Cells
3.1.8. Cancer Stem Cells
3.2. Glutamine
3.3. Tryptophan
3.4. Arginine
3.5. Methionine
3.6. Serine and Glycine
3.7. Cysteine
3.8. Alanine
3.9. Adenosine
3.10. Succinate and Itaconate
3.11. Exosomes
3.12. Lipids
3.13. Methylglyoxal
4. Concluding Remarks
Outstanding Questions |
|
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
5FU | 5-fluorouracil |
αKG | Alpha-ketoglutarate |
ACC-1 | Acetyl-CoA carboxylase-1 |
AHCY | Adenosylhomocysteinase |
AhR | Aryl hydrocarbon receptor |
ARG-1 | Arginase 1 |
ASS1 | Argininosuccinate synthetase 1 |
BCAA | Branched-chain amino acids |
CAF | Cancer-associated fibroblasts |
CD204 | Scavenger receptor A |
CRC | Colorectal cancer |
CSF3 | Colony stimulating factor 3 |
DC | Tumor resident dendritic cells |
DHAP | Dihydroxyacetone phosphate |
DON | 6-diazo-5-oxo-norleucine |
ETC | Electron transport chain |
EAA | Essential amino acid |
EMT | Epithelial to mesenchymal transition |
EV | Extracellular vesicle |
FAS | Fatty acid synthesis |
FAO | Fatty acid oxidation |
FAS | Fatty acid synthesis |
FoxP3 | Forkhead box P3 |
G3P | Glyceraldehyde-3-phosphate |
GLS | Glutaminase |
GLUT1 | Glucose transporter |
GSH | Glutathione |
HIF-1α/2α/3α, HIF-1β | Hypoxia inducible factors |
HK | Hexokinase |
IDH | Isocitrate dehydrogenase |
IDO | Indoleamine 2,3-dioxygenase |
IFNγ | Interferon-γ |
IRG1 | Cis-aconitate decarboxylase |
LAP | Laryngeal adductor paralysis |
LDHA/LDHB/LDH | Lactate dehydrogenase |
MAT2A | Methionine adenosyltransferase 2A |
MCT/MCT1/MCT4 | Monocarboxylate transporters |
MDSC | Myeloid-derived suppressor cells |
MYC | MYC proto-oncogene |
NEAA | Non-essential amino acid |
NFAT | Nuclear factor of activated T cells |
NK | Natural killer cell |
NO | Nitric Oxide |
NOS | Nitric oxide synthase |
NSCLC | Non-small cell lung cancer |
OXPHOS | Oxidative Phosphorylation |
PDAC | Pancreatic adenocarcinoma |
PD-1 | Programmed cell death protein 1 |
PD-L1 | Programmed death-ligand 1 |
PDH | Pyruvate dehydrogenase |
PDHK1 | Pyruvate dehydrogenase kinase |
PFK | Phosphofructokinase |
PGE2 | Prostaglandin E2 |
PHD | Prolyl-4-hydroxylase |
PI3K | Phosphoinositide 3-kinase |
PPAR | Peroxisome proliferator-activated receptors |
PPP | Pentose phosphate pathway |
ROS | Reactive oxygen species |
SAH | S-adenosylhomocysteine |
SAM | S-adenosylmethionine |
SDH | Succinate dehydrogenase |
SREBP | Sterol regulatory element binding proteins |
SUCLA2 | Succinyl CoA synthetase |
SUCNR1 | Succinate receptor 1 |
TAM | Tumor-associated macrophages |
TCA | Tricarboxylic acid cycle |
TCR | T cell receptor |
TDE | Tumor-derived exosome |
Teff | Effector T cells |
TET | Ten-eleven translocase |
TIL | Tumor-infiltrating lymphocytes |
TLR | Toll-like receptor |
TME | Tumor microenvironment |
Tmem | Memory T cells |
Treg | Regulatory T cells |
UPR | Unfolded protein response |
VEGF | Vascular endothelial growth factor |
References
- Warburg, O.; Wind, F.; Negelein, E. The Metabolism of Tumors in the Body. J. Gen. Physiol. 1927, 8, 519–530. [Google Scholar] [CrossRef] [PubMed]
- Warburg, O. On the origin of cancer cells. Science 1956, 123, 309–314. [Google Scholar] [CrossRef] [PubMed]
- Reitzer, L.J.; Wice, B.M.; Kennell, D. Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells. J. Biol. Chem. 1979, 254, 2669–2676. [Google Scholar] [CrossRef]
- Carrascosa, J.M.; Martínez, P.; Núñez de Castro, I. Nitrogen movement between host and tumor in mice inoculated with Ehrlich ascitic tumor cells. Cancer Res. 1984, 44, 3831–3835. [Google Scholar]
- Ma, G.; Zhang, Z.; Li, P.; Zeng, M.; Liang, Z.; Li, D.; Wang, L.; Chen, Y.; Liang, Y.; Niu, H. Reprogramming of glutamine metabolism and its impact on immune response in the tumor microenvironment. Cell Commun. Signal. 2022, 20, 114. [Google Scholar] [CrossRef] [PubMed]
- Li, A.M.; Ducker, G.S.; Li, Y.; Seoane, J.A.; Xiao, Y.; Melemenidis, S.; Zhou, Y.; Liu, L.; Vanharanta, S.; Graves, E.E.; et al. Metabolic Profiling Reveals a Dependency of Human Metastatic Breast Cancer on Mitochondrial Serine and One-Carbon Unit Metabolism. Mol. Cancer Res. 2020, 18, 599–611. [Google Scholar] [CrossRef]
- Abdul Kader, S.; Dib, S.; Achkar, I.W.; Thareja, G.; Suhre, K.; Rafii, A.; Halama, A. Defining the landscape of metabolic dysregulations in cancer metastasis. Clin. Exp. Metastasis 2022, 39, 345–362. [Google Scholar] [CrossRef]
- Elia, I.; Broekaert, D.; Christen, S.; Boon, R.; Radaelli, E.; Orth, M.F.; Verfaillie, C.; Grünewald, T.G.P.; Fendt, S.M. Proline metabolism supports metastasis formation and could be inhibited to selectively target metastasizing cancer cells. Nat. Commun. 2017, 8, 15267. [Google Scholar] [CrossRef] [PubMed]
- Du, F.; Chen, J.; Liu, H.; Cai, Y.; Cao, T.; Han, W.; Yi, X.; Qian, M.; Tian, D.; Nie, Y.; et al. SOX12 promotes colorectal cancer cell proliferation and metastasis by regulating asparagine synthesis. Cell Death Dis. 2019, 10, 239. [Google Scholar] [CrossRef] [PubMed]
- Chen, Y.J.; Mahieu, N.G.; Huang, X.; Singh, M.; Crawford, P.A.; Johnson, S.L.; Gross, R.W.; Schaefer, J.; Patti, G.J. Lactate metabolism is associated with mammalian mitochondria. Nat. Chem. Biol. 2016, 12, 937–943. [Google Scholar] [CrossRef]
- Mashimo, T.; Pichumani, K.; Vemireddy, V.; Hatanpaa, K.J.; Singh, D.K.; Sirasanagandla, S.; Nannepaga, S.; Piccirillo, S.G.; Kovacs, Z.; Foong, C.; et al. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell 2014, 159, 1603–1614. [Google Scholar] [CrossRef]
- Soula, M.; Unlu, G.; Welch, R.; Chudnovskiy, A.; Uygur, B.; Shah, V.; Alwaseem, H.; Bunk, P.; Subramanyam, V.; Yeh, H.W.; et al. Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer. Nature 2024, 633, 451–458. [Google Scholar] [CrossRef] [PubMed]
- Phan, L.M.; Yeung, S.C.; Lee, M.H. Cancer metabolic reprogramming: Importance, main features, and potentials for precise targeted anti-cancer therapies. Cancer Biol. Med. 2014, 11, 1–19. [Google Scholar] [CrossRef]
- Biswas, S.K. Metabolic Reprogramming of Immune Cells in Cancer Progression. Immunity 2015, 43, 435–449. [Google Scholar] [CrossRef] [PubMed]
- Dong, Y.; Tu, R.; Liu, H.; Qing, G. Regulation of cancer cell metabolism: Oncogenic MYC in the driver’s seat. Signal Transduct. Target. Ther. 2020, 5, 124. [Google Scholar] [CrossRef]
- Sachdeva, M.; Zhu, S.; Wu, F.; Wu, H.; Walia, V.; Kumar, S.; Elble, R.; Watabe, K.; Mo, Y.Y. p53 represses c-Myc through induction of the tumor suppressor miR-145. Proc. Natl. Acad. Sci. USA 2009, 106, 3207–3212. [Google Scholar] [CrossRef]
- Gan, B.; Lim, C.; Chu, G.; Hua, S.; Ding, Z.; Collins, M.; Hu, J.; Jiang, S.; Fletcher-Sananikone, E.; Zhuang, L.; et al. FoxOs enforce a progression checkpoint to constrain mTORC1-activated renal tumorigenesis. Cancer Cell 2010, 18, 472–484. [Google Scholar] [CrossRef] [PubMed]
- Kress, T.R.; Cannell, I.G.; Brenkman, A.B.; Samans, B.; Gaestel, M.; Roepman, P.; Burgering, B.M.; Bushell, M.; Rosenwald, A.; Eilers, M. The MK5/PRAK kinase and Myc form a negative feedback loop that is disrupted during colorectal tumorigenesis. Mol. Cell 2011, 41, 445–457. [Google Scholar] [CrossRef] [PubMed]
- Liu, P.; Ge, M.; Hu, J.; Li, X.; Che, L.; Sun, K.; Cheng, L.; Huang, Y.; Pilo, M.G.; Cigliano, A. A functional mammalian target of rapamycin complex 1 signaling is indispensable for c-Myc-driven hepatocarcinogenesis. Hepatology 2017, 66, 167–181. [Google Scholar] [CrossRef]
- Yue, M.; Jiang, J.; Gao, P.; Liu, H.; Qing, G. Oncogenic MYC Activates a Feedforward Regulatory Loop Promoting Essential Amino Acid Metabolism and Tumorigenesis. Cell Rep. 2017, 21, 3819–3832. [Google Scholar] [CrossRef] [PubMed]
- Hsieh, A.C.; Liu, Y.; Edlind, M.P.; Ingolia, N.T.; Janes, M.R.; Sher, A.; Shi, E.Y.; Stumpf, C.R.; Christensen, C.; Bonham, M.J.; et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 2012, 485, 55–61. [Google Scholar] [CrossRef]
- Wolfe, A.L.; Singh, K.; Zhong, Y.; Drewe, P.; Rajasekhar, V.K.; Sanghvi, V.R.; Mavrakis, K.J.; Jiang, M.; Roderick, J.E.; Van der Meulen, J.; et al. RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer. Nature 2014, 513, 65–70. [Google Scholar] [CrossRef]
- Dejure, F.R.; Royla, N.; Herold, S.; Kalb, J.; Walz, S.; Ade, C.P.; Mastrobuoni, G.; Vanselow, J.T.; Schlosser, A.; Wolf, E.; et al. The MYC mRNA 3′-UTR couples RNA polymerase II function to glutamine and ribonucleotide levels. EMBO J. 2017, 36, 1854–1868. [Google Scholar] [CrossRef] [PubMed]
- Tang, J.; Yan, T.; Bao, Y.; Shen, C.; Yu, C.; Zhu, X.; Tian, X.; Guo, F.; Liang, Q.; Liu, Q.; et al. LncRNA GLCC1 promotes colorectal carcinogenesis and glucose metabolism by stabilizing c-Myc. Nat. Commun. 2019, 10, 3499. [Google Scholar] [CrossRef] [PubMed]
- Xiao, Z.D.; Han, L.; Lee, H.; Zhuang, L.; Zhang, Y.; Baddour, J.; Nagrath, D.; Wood, C.G.; Gu, J.; Wu, X.; et al. Energy stress-induced lncRNA FILNC1 represses c-Myc-mediated energy metabolism and inhibits renal tumor development. Nat. Commun. 2017, 8, 783. [Google Scholar] [CrossRef] [PubMed]
- Yang, X.; Ye, H.; He, M.; Zhou, X.; Sun, N.; Guo, W.; Lin, X.; Huang, H.; Lin, Y.; Yao, R.; et al. LncRNA PDIA3P interacts with c-Myc to regulate cell proliferation via induction of pentose phosphate pathway in multiple myeloma. Biochem. Biophys. Res. Commun. 2018, 498, 207–213. [Google Scholar] [CrossRef] [PubMed]
- Chou, T.Y.; Hart, G.W.; Dang, C.V. c-Myc is glycosylated at threonine 58, a known phosphorylation site and a mutational hot spot in lymphomas. J. Biol. Chem. 1995, 270, 18961–18965. [Google Scholar] [CrossRef] [PubMed]
- Conacci-Sorrell, M.; Ngouenet, C.; Anderson, S.; Brabletz, T.; Eisenman, R.N. Stress-induced cleavage of Myc promotes cancer cell survival. Genes. Dev. 2014, 28, 689–707. [Google Scholar] [CrossRef] [PubMed]
- Burén, S.; Gomes, A.L.; Teijeiro, A.; Fawal, M.A.; Yilmaz, M.; Tummala, K.S.; Perez, M.; Rodriguez-Justo, M.; Campos-Olivas, R.; Megías, D.; et al. Regulation of OGT by URI in Response to Glucose Confers c-MYC-Dependent Survival Mechanisms. Cancer Cell 2016, 30, 290–307. [Google Scholar] [CrossRef] [PubMed]
- Nagao, A.; Kobayashi, M.; Koyasu, S.; Chow, C.C.T.; Harada, H. HIF-1-Dependent Reprogramming of Glucose Metabolic Pathway of Cancer Cells and Its Therapeutic Significance. Int. J. Mol. Sci. 2019, 20, 238. [Google Scholar] [CrossRef]
- Albadari, N.; Deng, S.; Li, W. The transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy. Expert Opin. Drug Discov. 2019, 14, 667–682. [Google Scholar] [CrossRef] [PubMed]
- Fukuda, R.; Zhang, H.; Kim, J.W.; Shimoda, L.; Dang, C.V.; Semenza, G.L. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell 2007, 129, 111–122. [Google Scholar] [CrossRef]
- Ivan, M.; Kondo, K.; Yang, H.; Kim, W.; Valiando, J.; Ohh, M.; Salic, A.; Asara, J.M.; Lane, W.S.; Kaelin, W.G. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: Implications for O2 sensing. Science 2001, 292, 464–468. [Google Scholar] [CrossRef]
- Jaakkola, P.; Mole, D.R.; Tian, Y.M.; Wilson, M.I.; Gielbert, J.; Gaskell, S.J.; von Kriegsheim, A.; Hebestreit, H.F.; Mukherji, M.; Schofield, C.J.; et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001, 292, 468–472. [Google Scholar] [CrossRef] [PubMed]
- Pérez-Escuredo, J.; Dadhich, R.K.; Dhup, S.; Cacace, A.; Van Hée, V.F.; De Saedeleer, C.J.; Sboarina, M.; Rodriguez, F.; Fontenille, M.J.; Brisson, L.; et al. Lactate promotes glutamine uptake and metabolism in oxidative cancer cells. Cell Cycle 2016, 15, 72–83. [Google Scholar] [CrossRef] [PubMed]
- Koshikawa, N.; Hayashi, J.; Nakagawara, A.; Takenaga, K. Reactive oxygen species-generating mitochondrial DNA mutation up-regulates hypoxia-inducible factor-1alpha gene transcription via phosphatidylinositol 3-kinase-Akt/protein kinase C/histone deacetylase pathway. J. Biol. Chem. 2009, 284, 33185–33194. [Google Scholar] [CrossRef] [PubMed]
- Martínez-Sáez, O.; Gajate Borau, P.; Alonso-Gordoa, T.; Molina-Cerrillo, J.; Grande, E. Targeting HIF-2 α in clear cell renal cell carcinoma: A promising therapeutic strategy. Crit. Rev. Oncol. Hematol. 2017, 111, 117–123. [Google Scholar] [CrossRef]
- Yang, F.; Zhang, H.; Mei, Y.; Wu, M. Reciprocal regulation of HIF-1α and lincRNA-p21 modulates the Warburg effect. Mol. Cell 2014, 53, 88–100. [Google Scholar] [CrossRef]
- Ohh, M.; Park, C.W.; Ivan, M.; Hoffman, M.A.; Kim, T.Y.; Huang, L.E.; Pavletich, N.; Chau, V.; Kaelin, W.G. Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat. Cell Biol. 2000, 2, 423–427. [Google Scholar] [CrossRef] [PubMed]
- Selak, M.A.; Armour, S.M.; MacKenzie, E.D.; Boulahbel, H.; Watson, D.G.; Mansfield, K.D.; Pan, Y.; Simon, M.C.; Thompson, C.B.; Gottlieb, E. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 2005, 7, 77–85. [Google Scholar] [CrossRef] [PubMed]
- Isaacs, J.S.; Jung, Y.J.; Mole, D.R.; Lee, S.; Torres-Cabala, C.; Chung, Y.L.; Merino, M.; Trepel, J.; Zbar, B.; Toro, J.; et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: Novel role of fumarate in regulation of HIF stability. Cancer Cell 2005, 8, 143–153. [Google Scholar] [CrossRef]
- Zeng, L.; Morinibu, A.; Kobayashi, M.; Zhu, Y.; Wang, X.; Goto, Y.; Yeom, C.J.; Zhao, T.; Hirota, K.; Shinomiya, K.; et al. Aberrant IDH3α expression promotes malignant tumor growth by inducing HIF-1-mediated metabolic reprogramming and angiogenesis. Oncogene 2015, 34, 4758–4766. [Google Scholar] [CrossRef] [PubMed]
- Fruman, D.A.; Chiu, H.; Hopkins, B.D.; Bagrodia, S.; Cantley, L.C.; Abraham, R.T. The PI3K Pathway in Human Disease. Cell 2017, 170, 605–635. [Google Scholar] [CrossRef] [PubMed]
- Lawrence, M.S.; Stojanov, P.; Mermel, C.H.; Robinson, J.T.; Garraway, L.A.; Golub, T.R.; Meyerson, M.; Gabriel, S.B.; Lander, E.S.; Getz, G. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 2014, 505, 495–501. [Google Scholar] [CrossRef] [PubMed]
- Hoxhaj, G.; Manning, B.D. The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat. Rev. Cancer 2020, 20, 74–88. [Google Scholar] [CrossRef] [PubMed]
- Elstrom, R.L.; Bauer, D.E.; Buzzai, M.; Karnauskas, R.; Harris, M.H.; Plas, D.R.; Zhuang, H.; Cinalli, R.M.; Alavi, A.; Rudin, C.M.; et al. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 2004, 64, 3892–3899. [Google Scholar] [CrossRef]
- Riquelme, I.; Pérez-Moreno, P.; Mora-Lagos, B.; Ili, C.; Brebi, P.; Roa, J.C. Long Non-Coding RNAs (lncRNAs) as Regulators of the PI3K/AKT/mTOR Pathway in Gastric Carcinoma. Int. J. Mol. Sci. 2023, 24, 6294. [Google Scholar] [CrossRef] [PubMed]
- Shiau, J.P.; Chuang, Y.T.; Yen, C.Y.; Chang, F.R.; Yang, K.H.; Hou, M.F.; Tang, J.Y.; Chang, H.W. Modulation of AKT Pathway-Targeting miRNAs for Cancer Cell Treatment with Natural Products. Int. J. Mol. Sci. 2023, 24, 3688. [Google Scholar] [CrossRef] [PubMed]
- Zhu, Q.Y.; He, Z.M.; Cao, W.M.; Li, B. The role of TSC2 in breast cancer: A literature review. Front. Oncol. 2023, 13, 1188371. [Google Scholar] [CrossRef] [PubMed]
- Keerthana, C.K.; Rayginia, T.P.; Shifana, S.C.; Anto, N.P.; Kalimuthu, K.; Isakov, N.; Anto, R.J. The role of AMPK in cancer metabolism and its impact on the immunomodulation of the tumor microenvironment. Front. Immunol. 2023, 14, 1114582. [Google Scholar] [CrossRef] [PubMed]
- Hawley, S.A.; Boudeau, J.; Reid, J.L.; Mustard, K.J.; Udd, L.; Mäkelä, T.P.; Alessi, D.R.; Hardie, D.G. Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J. Biol. 2003, 2, 28. [Google Scholar] [CrossRef]
- Woods, A.; Dickerson, K.; Heath, R.; Hong, S.P.; Momcilovic, M.; Johnstone, S.R.; Carlson, M.; Carling, D. Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2005, 2, 21–33. [Google Scholar] [CrossRef]
- Hawley, S.A.; Ross, F.A.; Gowans, G.J.; Tibarewal, P.; Leslie, N.R.; Hardie, D.G. Phosphorylation by Akt within the ST loop of AMPK-α1 down-regulates its activation in tumour cells. Biochem. J. 2014, 459, 275–287. [Google Scholar] [CrossRef] [PubMed]
- Ling, N.X.Y.; Kaczmarek, A.; Hoque, A.; Davie, E.; Ngoei, K.R.W.; Morrison, K.R.; Smiles, W.J.; Forte, G.M.; Wang, T.; Lie, S.; et al. mTORC1 directly inhibits AMPK to promote cell proliferation under nutrient stress. Nat. Metab. 2020, 2, 41–49. [Google Scholar] [CrossRef]
- Zhou, W.; Zhang, J.; Marcus, A.I. LKB1 Tumor Suppressor: Therapeutic Opportunities Knock when LKB1 Is Inactivated. Genes Dis. 2014, 1, 64–74. [Google Scholar] [CrossRef] [PubMed]
- Liu, X.; Xiao, Z.D.; Han, L.; Zhang, J.; Lee, S.W.; Wang, W.; Lee, H.; Zhuang, L.; Chen, J.; Lin, H.K.; et al. LncRNA NBR2 engages a metabolic checkpoint by regulating AMPK under energy stress. Nat. Cell Biol. 2016, 18, 431–442. [Google Scholar] [CrossRef]
- Fogarty, S.; Ross, F.A.; Vara Ciruelos, D.; Gray, A.; Gowans, G.J.; Hardie, D.G. AMPK Causes Cell Cycle Arrest in LKB1-Deficient Cells via Activation of CAMKK2. Mol. Cancer Res. 2016, 14, 683–695. [Google Scholar] [CrossRef]
- El-Masry, O.S.; Brown, B.L.; Dobson, P.R. Effects of activation of AMPK on human breast cancer cell lines with different genetic backgrounds. Oncol. Lett. 2012, 3, 224–228. [Google Scholar] [CrossRef] [PubMed]
- Song, X.; Kim, S.Y.; Zhang, L.; Tang, D.; Bartlett, D.L.; Kwon, Y.T.; Lee, Y.J. Role of AMP-activated protein kinase in cross-talk between apoptosis and autophagy in human colon cancer. Cell Death Dis. 2014, 5, e1504. [Google Scholar] [CrossRef]
- Blagih, J.; Coulombe, F.; Vincent, E.E.; Dupuy, F.; Galicia-Vázquez, G.; Yurchenko, E.; Raissi, T.C.; van der Windt, G.J.; Viollet, B.; Pearce, E.L.; et al. The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity 2015, 42, 41–54. [Google Scholar] [CrossRef] [PubMed]
- Dabi, Y.T.; Andualem, H.; Degechisa, S.T.; Gizaw, S.T. Targeting Metabolic Reprogramming of T-Cells for Enhanced Anti-Tumor Response. Biologics 2022, 16, 35–45. [Google Scholar] [CrossRef] [PubMed]
- Rao, E.; Zhang, Y.; Zhu, G.; Hao, J.; Persson, X.M.; Egilmez, N.K.; Suttles, J.; Li, B. Deficiency of AMPK in CD8+ T cells suppresses their anti-tumor function by inducing protein phosphatase-mediated cell death. Oncotarget 2015, 6, 7944–7958. [Google Scholar] [CrossRef]
- Sag, D.; Carling, D.; Stout, R.D.; Suttles, J. Adenosine 5′-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J. Immunol. 2008, 181, 8633–8641. [Google Scholar] [CrossRef]
- Chiang, C.F.; Chao, T.T.; Su, Y.F.; Hsu, C.C.; Chien, C.Y.; Chiu, K.C.; Shiah, S.G.; Lee, C.H.; Liu, S.Y.; Shieh, Y.S. Metformin-treated cancer cells modulate macrophage polarization through AMPK-NF-κB signaling. Oncotarget 2017, 8, 20706–20718. [Google Scholar] [CrossRef] [PubMed]
- Kim, J. Regulation of Immune Cell Functions by Metabolic Reprogramming. J. Immunol. Res. 2018, 2018, 8605471. [Google Scholar] [CrossRef] [PubMed]
- Gomes, A.P.; Blenis, J. A nexus for cellular homeostasis: The interplay between metabolic and signal transduction pathways. Curr. Opin. Biotechnol. 2015, 34, 110–117. [Google Scholar] [CrossRef] [PubMed]
- El Khayari, A.; Bouchmaa, N.; Taib, B.; Wei, Z.; Zeng, A.; El Fatimy, R. Metabolic Rewiring in Glioblastoma Cancer: EGFR, IDH and Beyond. Front. Oncol. 2022, 12, 901951. [Google Scholar] [CrossRef] [PubMed]
- Ying, H.; Kimmelman, A.C.; Lyssiotis, C.A.; Hua, S.; Chu, G.C.; Fletcher-Sananikone, E.; Locasale, J.W.; Son, J.; Zhang, H.; Coloff, J.L.; et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 2012, 149, 656–670. [Google Scholar] [CrossRef]
- Mukhopadhyay, S.; Vander Heiden, M.G.; McCormick, F. The Metabolic Landscape of RAS-Driven Cancers from biology to therapy. Nat. Cancer 2021, 2, 271–283. [Google Scholar] [CrossRef]
- Gaglio, D.; Metallo, C.M.; Gameiro, P.A.; Hiller, K.; Danna, L.S.; Balestrieri, C.; Alberghina, L.; Stephanopoulos, G.; Chiaradonna, F. Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth. Mol. Syst. Biol. 2011, 7, 523. [Google Scholar] [CrossRef]
- Son, J.; Lyssiotis, C.A.; Ying, H.; Wang, X.; Hua, S.; Ligorio, M.; Perera, R.M.; Ferrone, C.R.; Mullarky, E.; Shyh-Chang, N.; et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 2013, 496, 101–105. [Google Scholar] [CrossRef] [PubMed]
- Moran, D.M.; Trusk, P.B.; Pry, K.; Paz, K.; Sidransky, D.; Bacus, S.S. KRAS mutation status is associated with enhanced dependency on folate metabolism pathways in non-small cell lung cancer cells. Mol. Cancer Ther. 2014, 13, 1611–1624. [Google Scholar] [CrossRef]
- Sullivan, M.R.; Vander Heiden, M.G. Determinants of nutrient limitation in cancer. Crit. Rev. Biochem. Mol. Biol. 2019, 54, 193–207. [Google Scholar] [CrossRef] [PubMed]
- Siska, P.J.; Rathmell, J.C. T cell metabolic fitness in antitumor immunity. Trends Immunol. 2015, 36, 257–264. [Google Scholar] [CrossRef]
- Arner, E.N.; Rathmell, J.C. Metabolic programming and immune suppression in the tumor microenvironment. Cancer Cell 2023, 41, 421–433. [Google Scholar] [CrossRef] [PubMed]
- Wang, K.; Lu, Y.; Li, H.; Zhang, J.; Ju, Y.; Ouyang, M. Role of long non-coding RNAs in metabolic reprogramming of gastrointestinal cancer cells. Cancer Cell Int. 2024, 24, 15. [Google Scholar] [CrossRef] [PubMed]
- Lin, W.; Zhou, Q.; Wang, C.Q.; Zhu, L.; Bi, C.; Zhang, S.; Wang, X.; Jin, H. LncRNAs regulate metabolism in cancer. Int. J. Biol. Sci. 2020, 16, 1194–1206. [Google Scholar] [CrossRef]
- Jin, L.; Alesi, G.N.; Kang, S. Glutaminolysis as a target for cancer therapy. Oncogene 2016, 35, 3619–3625. [Google Scholar] [CrossRef] [PubMed]
- Roos, D.; Loos, J.A. Changes in the carbohydrate metabolism of mitogenically stimulated human peripheral lymphocytes. II. Relative importance of glycolysis and oxidative phosphorylation on phytohaemagglutinin stimulation. Exp. Cell Res. 1973, 77, 127–135. [Google Scholar] [CrossRef] [PubMed]
- Reinfeld, B.I.; Madden, M.Z.; Wolf, M.M.; Chytil, A.; Bader, J.E.; Patterson, A.R.; Sugiura, A.; Cohen, A.S.; Ali, A.; Do, B.T.; et al. Cell-programmed nutrient partitioning in the tumour microenvironment. Nature 2021, 593, 282–288. [Google Scholar] [CrossRef]
- Melkonian, E.A.; Schury, M.P. Biochemistry, Anaerobic Glycolysis; StatPearls National Library of Medicine: Treasure Island, FL, USA, 8 August 2022. [Google Scholar]
- Jin, L.; Zhou, Y. Crucial role of the pentose phosphate pathway in malignant tumors. Oncol. Lett. 2019, 17, 4213–4221. [Google Scholar] [CrossRef]
- Sullivan, M.R.; Danai, L.V.; Lewis, C.A.; Chan, S.H.; Gui, D.Y.; Kunchok, T.; Dennstedt, E.A.; Vander Heiden, M.G.; Muir, A. Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability. Elife 2019, 8, e44235. [Google Scholar] [CrossRef]
- Chang, C.H.; Curtis, J.D.; Maggi, L.B.; Faubert, B.; Villarino, A.V.; O’Sullivan, D.; Huang, S.C.; van der Windt, G.J.; Blagih, J.; Qiu, J.; et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 2013, 153, 1239–1251. [Google Scholar] [CrossRef]
- Chang, C.H.; Qiu, J.; O’Sullivan, D.; Buck, M.D.; Noguchi, T.; Curtis, J.D.; Chen, Q.; Gindin, M.; Gubin, M.M.; van der Windt, G.J.; et al. Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. Cell 2015, 162, 1229–1241. [Google Scholar] [CrossRef] [PubMed]
- Macintyre, A.N.; Gerriets, V.A.; Nichols, A.G.; Michalek, R.D.; Rudolph, M.C.; Deoliveira, D.; Anderson, S.M.; Abel, E.D.; Chen, B.J.; Hale, L.P.; et al. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab. 2014, 20, 61–72. [Google Scholar] [CrossRef] [PubMed]
- Watson, M.J.; Vignali, P.D.A.; Mullett, S.J.; Overacre-Delgoffe, A.E.; Peralta, R.M.; Grebinoski, S.; Menk, A.V.; Rittenhouse, N.L.; DePeaux, K.; Whetstone, R.D.; et al. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature 2021, 591, 645–651. [Google Scholar] [CrossRef] [PubMed]
- Li, W.; Tanikawa, T.; Kryczek, I.; Xia, H.; Li, G.; Wu, K.; Wei, S.; Zhao, L.; Vatan, L.; Wen, B.; et al. Aerobic Glycolysis Controls Myeloid-Derived Suppressor Cells and Tumor Immunity via a Specific CEBPB Isoform in Triple-Negative Breast Cancer. Cell Metab. 2018, 28, 87–103.e6. [Google Scholar] [CrossRef]
- Kiss, K.; Baghy, K.; Spisák, S.; Szanyi, S.; Tulassay, Z.; Zalatnai, A.; Löhr, J.M.; Jesenofsky, R.; Kovalszky, I.; Firneisz, G. Chronic hyperglycemia induces trans-differentiation of human pancreatic stellate cells and enhances the malignant molecular communication with human pancreatic cancer cells. PLoS ONE 2015, 10, e0128059. [Google Scholar] [CrossRef] [PubMed]
- Ippolito, L.; Comito, G.; Parri, M.; Iozzo, M.; Duatti, A.; Virgilio, F.; Lorito, N.; Bacci, M.; Pardella, E.; Sandrini, G.; et al. Lactate Rewires Lipid Metabolism and Sustains a Metabolic-Epigenetic Axis in Prostate Cancer. Cancer Res. 2022, 82, 1267–1282. [Google Scholar] [CrossRef]
- Ippolito, L.; Morandi, A.; Giannoni, E.; Chiarugi, P. Lactate: A Metabolic Driver in the Tumour Landscape. Trends Biochem. Sci. 2019, 44, 153–166. [Google Scholar] [CrossRef] [PubMed]
- Walenta, S.; Wetterling, M.; Lehrke, M.; Schwickert, G.; Sundfør, K.; Rofstad, E.K.; Mueller-Klieser, W. High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res. 2000, 60, 916–921. [Google Scholar] [PubMed]
- Brizel, D.M.; Schroeder, T.; Scher, R.L.; Walenta, S.; Clough, R.W.; Dewhirst, M.W.; Mueller-Klieser, W. Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. Int. J. Radiat. Oncol. Biol. Phys. 2001, 51, 349–353. [Google Scholar] [CrossRef]
- Feng, Y.; Xiong, Y.; Qiao, T.; Li, X.; Jia, L.; Han, Y. Lactate dehydrogenase A: A key player in carcinogenesis and potential target in cancer therapy. Cancer Med. 2018, 7, 6124–6136. [Google Scholar] [CrossRef]
- Pérez-Tomás, R.; Pérez-Guillén, I. Lactate in the Tumor Microenvironment: An Essential Molecule in Cancer Progression and Treatment. Cancers 2020, 12, 3244. [Google Scholar] [CrossRef] [PubMed]
- Hui, S.; Ghergurovich, J.M.; Morscher, R.J.; Jang, C.; Teng, X.; Lu, W.; Esparza, L.A.; Reya, T.; Zhan, L.; Guo, Y.; et al. Glucose feeds the TCA cycle via circulating lactate. Nature 2017, 551, 115–118. [Google Scholar] [CrossRef] [PubMed]
- Sonveaux, P.; Végran, F.; Schroeder, T.; Wergin, M.C.; Verrax, J.; Rabbani, Z.N.; De Saedeleer, C.J.; Kennedy, K.M.; Diepart, C.; Jordan, B.F.; et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J. Clin. Investig. 2008, 118, 3930–3942. [Google Scholar] [CrossRef]
- Park, S.; Chang, C.Y.; Safi, R.; Liu, X.; Baldi, R.; Jasper, J.S.; Anderson, G.R.; Liu, T.; Rathmell, J.C.; Dewhirst, M.W.; et al. ERRα-Regulated Lactate Metabolism Contributes to Resistance to Targeted Therapies in Breast Cancer. Cell Rep. 2016, 15, 323–335. [Google Scholar] [CrossRef]
- Barbieri, L.; Veliça, P.; Gameiro, P.A.; Cunha, P.P.; Foskolou, I.P.; Rullman, E.; Bargiela, D.; Johnson, R.S.; Rundqvist, H. Lactate exposure shapes the metabolic and transcriptomic profile of CD8+ T cells. Front. Immunol. 2023, 14, 1101433. [Google Scholar] [CrossRef]
- de la Cruz-López, K.G.; Castro-Muñoz, L.J.; Reyes-Hernández, D.O.; García-Carrancá, A.; Manzo-Merino, J. Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches. Front. Oncol. 2019, 9, 1143. [Google Scholar] [CrossRef] [PubMed]
- Kennedy, K.M.; Scarbrough, P.M.; Ribeiro, A.; Richardson, R.; Yuan, H.; Sonveaux, P.; Landon, C.D.; Chi, J.T.; Pizzo, S.; Schroeder, T.; et al. Catabolism of exogenous lactate reveals it as a legitimate metabolic substrate in breast cancer. PLoS ONE 2013, 8, e75154. [Google Scholar] [CrossRef] [PubMed]
- Tasdogan, A.; Faubert, B.; Ramesh, V.; Ubellacker, J.M.; Shen, B.; Solmonson, A.; Murphy, M.M.; Gu, Z.; Gu, W.; Martin, M.; et al. Metabolic heterogeneity confers differences in melanoma metastatic potential. Nature 2020, 577, 115–120. [Google Scholar] [CrossRef] [PubMed]
- Kozlov, A.M.; Lone, A.; Betts, D.H.; Cumming, R.C. Lactate preconditioning promotes a HIF-1α-mediated metabolic shift from OXPHOS to glycolysis in normal human diploid fibroblasts. Sci. Rep. 2020, 10, 8388. [Google Scholar] [CrossRef] [PubMed]
- Menk, A.V.; Scharping, N.E.; Moreci, R.S.; Zeng, X.; Guy, C.; Salvatore, S.; Bae, H.; Xie, J.; Young, H.A.; Wendell, S.G.; et al. Early TCR Signaling Induces Rapid Aerobic Glycolysis Enabling Distinct Acute T Cell Effector Functions. Cell Rep. 2018, 22, 1509–1521. [Google Scholar] [CrossRef] [PubMed]
- Klein Geltink, R.I.; O’Sullivan, D.; Corrado, M.; Bremser, A.; Buck, M.D.; Buescher, J.M.; Firat, E.; Zhu, X.; Niedermann, G.; Caputa, G.; et al. Mitochondrial Priming by CD28. Cell 2017, 171, 385–397.e311. [Google Scholar] [CrossRef]
- Waickman, A.T.; Powell, J.D. mTOR, metabolism, and the regulation of T-cell differentiation and function. Immunol. Rev. 2012, 249, 43–58. [Google Scholar] [CrossRef]
- Fischer, K.; Hoffmann, P.; Voelkl, S.; Meidenbauer, N.; Ammer, J.; Edinger, M.; Gottfried, E.; Schwarz, S.; Rothe, G.; Hoves, S.; et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 2007, 109, 3812–3819. [Google Scholar] [CrossRef] [PubMed]
- Siska, P.J.; Beckermann, K.E.; Mason, F.M.; Andrejeva, G.; Greenplate, A.R.; Sendor, A.B.; Chiang, Y.J.; Corona, A.L.; Gemta, L.F.; Vincent, B.G.; et al. Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma. JCI Insight 2017, 2, e93411. [Google Scholar] [CrossRef]
- Brand, A.; Singer, K.; Koehl, G.E.; Kolitzus, M.; Schoenhammer, G.; Thiel, A.; Matos, C.; Bruss, C.; Klobuch, S.; Peter, K.; et al. LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells. Cell Metab. 2016, 24, 657–671. [Google Scholar] [CrossRef] [PubMed]
- Leite, T.C.; Coelho, R.G.; Da Silva, D.; Coelho, W.S.; Marinho-Carvalho, M.M.; Sola-Penna, M. Lactate downregulates the glycolytic enzymes hexokinase and phosphofructokinase in diverse tissues from mice. FEBS Lett. 2011, 585, 92–98. [Google Scholar] [CrossRef]
- DePeaux, K.; Delgoffe, G.M. Metabolic barriers to cancer immunotherapy. Nat. Rev. Immunol. 2021, 21, 785–797. [Google Scholar] [CrossRef] [PubMed]
- Vaeth, M.; Feske, S. NFAT control of immune function: New Frontiers for an Abiding Trooper. F1000Res 2018, 7, 260. [Google Scholar] [CrossRef]
- Haas, R.; Smith, J.; Rocher-Ros, V.; Nadkarni, S.; Montero-Melendez, T.; D’Acquisto, F.; Bland, E.J.; Bombardieri, M.; Pitzalis, C.; Perretti, M.; et al. Lactate Regulates Metabolic and Pro-inflammatory Circuits in Control of T Cell Migration and Effector Functions. PLoS Biol. 2015, 13, e1002202. [Google Scholar] [CrossRef] [PubMed]
- Angelin, A.; Gil-de-Gómez, L.; Dahiya, S.; Jiao, J.; Guo, L.; Levine, M.H.; Wang, Z.; Quinn, W.J.; Kopinski, P.K.; Wang, L.; et al. Foxp3 Reprograms T Cell Metabolism to Function in Low-Glucose, High-Lactate Environments. Cell Metab. 2017, 25, 1282–1293.e1287. [Google Scholar] [CrossRef] [PubMed]
- Weinberg, S.E.; Singer, B.D.; Steinert, E.M.; Martinez, C.A.; Mehta, M.M.; Martínez-Reyes, I.; Gao, P.; Helmin, K.A.; Abdala-Valencia, H.; Sena, L.A.; et al. Mitochondrial complex III is essential for suppressive function of regulatory T cells. Nature 2019, 565, 495–499. [Google Scholar] [CrossRef] [PubMed]
- Shi, L.Z.; Wang, R.; Huang, G.; Vogel, P.; Neale, G.; Green, D.R.; Chi, H. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med. 2011, 208, 1367–1376. [Google Scholar] [CrossRef] [PubMed]
- Kumagai, S.; Koyama, S.; Itahashi, K.; Tanegashima, T.; Lin, Y.T.; Togashi, Y.; Kamada, T.; Irie, T.; Okumura, G.; Kono, H.; et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell 2022, 40, 201–218.e209. [Google Scholar] [CrossRef] [PubMed]
- Puthenveetil, A.; Dubey, S. Metabolic reprograming of tumor-associated macrophages. Ann. Transl. Med. 2020, 8, 1030. [Google Scholar] [CrossRef]
- Colegio, O.R.; Chu, N.Q.; Szabo, A.L.; Chu, T.; Rhebergen, A.M.; Jairam, V.; Cyrus, N.; Brokowski, C.E.; Eisenbarth, S.C.; Phillips, G.M.; et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 2014, 513, 559–563. [Google Scholar] [CrossRef] [PubMed]
- Zhang, D.; Tang, Z.; Huang, H.; Zhou, G.; Cui, C.; Weng, Y.; Liu, W.; Kim, S.; Lee, S.; Perez-Neut, M.; et al. Metabolic regulation of gene expression by histone lactylation. Nature 2019, 574, 575–580. [Google Scholar] [CrossRef]
- Liu, N.; Luo, J.; Kuang, D.; Xu, S.; Duan, Y.; Xia, Y.; Wei, Z.; Xie, X.; Yin, B.; Chen, F.; et al. Lactate inhibits ATP6V0d2 expression in tumor-associated macrophages to promote HIF-2α-mediated tumor progression. J. Clin. Investig. 2019, 129, 631–646. [Google Scholar] [CrossRef] [PubMed]
- Shan, T.; Chen, S.; Chen, X.; Wu, T.; Yang, Y.; Li, S.; Ma, J.; Zhao, J.; Lin, W.; Li, W.; et al. M2-TAM subsets altered by lactic acid promote T-cell apoptosis through the PD-L1/PD-1 pathway. Oncol. Rep. 2020, 44, 1885–1894. [Google Scholar] [CrossRef]
- Martinez-Outschoorn, U.E.; Lisanti, M.P.; Sotgia, F. Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth. Semin. Cancer Biol. 2014, 25, 47–60. [Google Scholar] [CrossRef] [PubMed]
- Becker, L.M.; O’Connell, J.T.; Vo, A.P.; Cain, M.P.; Tampe, D.; Bizarro, L.; Sugimoto, H.; McGow, A.K.; Asara, J.M.; Lovisa, S.; et al. Epigenetic Reprogramming of Cancer-Associated Fibroblasts Deregulates Glucose Metabolism and Facilitates Progression of Breast Cancer. Cell Rep. 2020, 31, 107701. [Google Scholar] [CrossRef] [PubMed]
- Fiaschi, T.; Marini, A.; Giannoni, E.; Taddei, M.L.; Gandellini, P.; De Donatis, A.; Lanciotti, M.; Serni, S.; Cirri, P.; Chiarugi, P. Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay. Cancer Res. 2012, 72, 5130–5140. [Google Scholar] [CrossRef]
- Gottfried, E.; Kunz-Schughart, L.A.; Ebner, S.; Mueller-Klieser, W.; Hoves, S.; Andreesen, R.; Mackensen, A.; Kreutz, M. Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood 2006, 107, 2013–2021. [Google Scholar] [CrossRef] [PubMed]
- Payen, V.L.; Mina, E.; Van Hée, V.F.; Porporato, P.E.; Sonveaux, P. Monocarboxylate transporters in cancer. Mol. Metab. 2020, 33, 48–66. [Google Scholar] [CrossRef]
- Guido, C.; Whitaker-Menezes, D.; Capparelli, C.; Balliet, R.; Lin, Z.; Pestell, R.G.; Howell, A.; Aquila, S.; Andò, S.; Martinez-Outschoorn, U.; et al. Metabolic reprogramming of cancer-associated fibroblasts by TGF-β drives tumor growth: Connecting TGF-β signaling with “Warburg-like” cancer metabolism and L-lactate production. Cell Cycle 2012, 11, 3019–3035. [Google Scholar] [CrossRef] [PubMed]
- Krawczyk, C.M.; Holowka, T.; Sun, J.; Blagih, J.; Amiel, E.; DeBerardinis, R.J.; Cross, J.R.; Jung, E.; Thompson, C.B.; Jones, R.G.; et al. Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood 2010, 115, 4742–4749. [Google Scholar] [CrossRef] [PubMed]
- Pearce, E.J.; Everts, B. Dendritic cell metabolism. Nat. Rev. Immunol. 2015, 15, 18–29. [Google Scholar] [CrossRef] [PubMed]
- Nasi, A.; Fekete, T.; Krishnamurthy, A.; Snowden, S.; Rajnavölgyi, E.; Catrina, A.I.; Wheelock, C.E.; Vivar, N.; Rethi, B. Dendritic cell reprogramming by endogenously produced lactic acid. J. Immunol. 2013, 191, 3090–3099. [Google Scholar] [CrossRef]
- Kim, J.; Lee, H.; Choi, H.K.; Min, H. Discovery of Myeloid-Derived Suppressor Cell-Specific Metabolism by Metabolomic and Lipidomic Profiling. Metabolites 2023, 13, 477. [Google Scholar] [CrossRef] [PubMed]
- Yang, X.; Lu, Y.; Hang, J.; Zhang, J.; Zhang, T.; Huo, Y.; Liu, J.; Lai, S.; Luo, D.; Wang, L.; et al. Lactate-Modulated Immunosuppression of Myeloid-Derived Suppressor Cells Contributes to the Radioresistance of Pancreatic Cancer. Cancer Immunol. Res. 2020, 8, 1440–1451. [Google Scholar] [CrossRef] [PubMed]
- Liao, J.; Qian, F.; Tchabo, N.; Mhawech-Fauceglia, P.; Beck, A.; Qian, Z.; Wang, X.; Huss, W.J.; Lele, S.B.; Morrison, C.D.; et al. Ovarian cancer spheroid cells with stem cell-like properties contribute to tumor generation, metastasis and chemotherapy resistance through hypoxia-resistant metabolism. PLoS ONE 2014, 9, e84941. [Google Scholar] [CrossRef] [PubMed]
- Liu, P.P.; Liao, J.; Tang, Z.J.; Wu, W.J.; Yang, J.; Zeng, Z.L.; Hu, Y.; Wang, P.; Ju, H.Q.; Xu, R.H.; et al. Metabolic regulation of cancer cell side population by glucose through activation of the Akt pathway. Cell Death Differ. 2014, 21, 124–135. [Google Scholar] [CrossRef] [PubMed]
- Ciavardelli, D.; Rossi, C.; Barcaroli, D.; Volpe, S.; Consalvo, A.; Zucchelli, M.; De Cola, A.; Scavo, E.; Carollo, R.; D’Agostino, D.; et al. Breast cancer stem cells rely on fermentative glycolysis and are sensitive to 2-deoxyglucose treatment. Cell Death Dis. 2014, 5, e1336. [Google Scholar] [CrossRef] [PubMed]
- Palorini, R.; Votta, G.; Balestrieri, C.; Monestiroli, A.; Olivieri, S.; Vento, R.; Chiaradonna, F. Energy metabolism characterization of a novel cancer stem cell-like line 3AB-OS. J. Cell Biochem. 2014, 115, 368–379. [Google Scholar] [CrossRef]
- Lacey, J.M.; Wilmore, D.W. Is glutamine a conditionally essential amino acid? Nutr. Rev. 1990, 48, 297–309. [Google Scholar] [CrossRef]
- DeBerardinis, R.J.; Mancuso, A.; Daikhin, E.; Nissim, I.; Yudkoff, M.; Wehrli, S.; Thompson, C.B. Beyond aerobic glycolysis: Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc. Natl. Acad. Sci. USA 2007, 104, 19345–19350. [Google Scholar] [CrossRef]
- Chaudhry, F.A.; Reimer, R.J.; Edwards, R.H. The glutamine commute: Take the N line and transfer to the A. J. Cell Biol. 2002, 157, 349–355. [Google Scholar] [CrossRef] [PubMed]
- Nicklin, P.; Bergman, P.; Zhang, B.; Triantafellow, E.; Wang, H.; Nyfeler, B.; Yang, H.; Hild, M.; Kung, C.; Wilson, C.; et al. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 2009, 136, 521–534. [Google Scholar] [CrossRef] [PubMed]
- Qing, G.; Li, B.; Vu, A.; Skuli, N.; Walton, Z.E.; Liu, X.; Mayes, P.A.; Wise, D.R.; Thompson, C.B.; Maris, J.M.; et al. ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation. Cancer Cell 2012, 22, 631–644. [Google Scholar] [CrossRef]
- Ma, Z.; Ye, W.; Wang, J.; Huang, X.; Huang, J.; Li, X.; Hu, C.; Li, C.; Zhou, Y.; Lin, X.; et al. Glutamate dehydrogenase 1: A novel metabolic target in inhibiting acute myeloid leukaemia progression. Br. J. Haematol. 2023, 202, 566–577. [Google Scholar] [CrossRef] [PubMed]
- Cox, A.G.; Hwang, K.L.; Brown, K.K.; Evason, K.; Beltz, S.; Tsomides, A.; O’Connor, K.; Galli, G.G.; Yimlamai, D.; Chhangawala, S.; et al. Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth. Nat. Cell Biol. 2016, 18, 886–896. [Google Scholar] [CrossRef] [PubMed]
- Mukhopadhyay, S.; Goswami, D.; Adiseshaiah, P.P.; Burgan, W.; Yi, M.; Guerin, T.M.; Kozlov, S.V.; Nissley, D.V.; McCormick, F. Undermining Glutaminolysis Bolsters Chemotherapy While NRF2 Promotes Chemoresistance in KRAS-Driven Pancreatic Cancers. Cancer Res. 2020, 80, 1630–1643. [Google Scholar] [CrossRef] [PubMed]
- Mitsuishi, Y.; Taguchi, K.; Kawatani, Y.; Shibata, T.; Nukiwa, T.; Aburatani, H.; Yamamoto, M.; Motohashi, H. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 2012, 22, 66–79. [Google Scholar] [CrossRef]
- Schulte, M.L.; Fu, A.; Zhao, P.; Li, J.; Geng, L.; Smith, S.T.; Kondo, J.; Coffey, R.J.; Johnson, M.O.; Rathmell, J.C.; et al. Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models. Nat. Med. 2018, 24, 194–202. [Google Scholar] [CrossRef] [PubMed]
- Leone, R.D.; Zhao, L.; Englert, J.M.; Sun, I.M.; Oh, M.H.; Sun, I.H.; Arwood, M.L.; Bettencourt, I.A.; Patel, C.H.; Wen, J.; et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 2019, 366, 1013–1021. [Google Scholar] [CrossRef] [PubMed]
- Yang, L.; Achreja, A.; Yeung, T.L.; Mangala, L.S.; Jiang, D.; Han, C.; Baddour, J.; Marini, J.C.; Ni, J.; Nakahara, R.; et al. Targeting Stromal Glutamine Synthetase in Tumors Disrupts Tumor Microenvironment-Regulated Cancer Cell Growth. Cell Metab. 2016, 24, 685–700. [Google Scholar] [CrossRef]
- Oh, M.H.; Sun, I.H.; Zhao, L.; Leone, R.D.; Sun, I.M.; Xu, W.; Collins, S.L.; Tam, A.J.; Blosser, R.L.; Patel, C.H.; et al. Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells. J. Clin. Investig. 2020, 130, 3865–3884. [Google Scholar] [CrossRef]
- Newsholme, P. Why is L-glutamine metabolism important to cells of the immune system in health, postinjury, surgery or infection? J. Nutr. 2001, 131, 2515S–2522S; discussion 2523S–2514S. [Google Scholar] [CrossRef] [PubMed]
- Liu, P.S.; Wang, H.; Li, X.; Chao, T.; Teav, T.; Christen, S.; Di Conza, G.; Cheng, W.C.; Chou, C.H.; Vavakova, M.; et al. α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat. Immunol. 2017, 18, 985–994. [Google Scholar] [CrossRef]
- Xu, T.; Stewart, K.M.; Wang, X.; Liu, K.; Xie, M.; Ryu, J.K.; Li, K.; Ma, T.; Wang, H.; Ni, L.; et al. Metabolic control of T. Nature 2017, 548, 228–233. [Google Scholar] [CrossRef]
- Loftus, R.M.; Assmann, N.; Kedia-Mehta, N.; O’Brien, K.L.; Garcia, A.; Gillespie, C.; Hukelmann, J.L.; Oefner, P.J.; Lamond, A.I.; Gardiner, C.M.; et al. Amino acid-dependent cMyc expression is essential for NK cell metabolic and functional responses in mice. Nat. Commun. 2018, 9, 2341. [Google Scholar] [CrossRef]
- Gregory, M.A.; Hann, S.R. c-Myc proteolysis by the ubiquitin-proteasome pathway: Stabilization of c-Myc in Burkitt’s lymphoma cells. Mol. Cell Biol. 2000, 20, 2423–2435. [Google Scholar] [CrossRef]
- Gao, P.; Tchernyshyov, I.; Chang, T.C.; Lee, Y.S.; Kita, K.; Ochi, T.; Zeller, K.I.; De Marzo, A.M.; Van Eyk, J.E.; Mendell, J.T.; et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 2009, 458, 762–765. [Google Scholar] [CrossRef]
- Brombacher, E.C.; Everts, B. Shaping of Dendritic Cell Function by the Metabolic Micro-Environment. Front. Endocrinol. 2020, 11, 555. [Google Scholar] [CrossRef] [PubMed]
- Aguilar, E.; Marin de Mas, I.; Zodda, E.; Marin, S.; Morrish, F.; Selivanov, V.; Meca-Cortés, Ó.; Delowar, H.; Pons, M.; Izquierdo, I.; et al. Metabolic Reprogramming and Dependencies Associated with Epithelial Cancer Stem Cells Independent of the Epithelial-Mesenchymal Transition Program. Stem. Cells 2016, 34, 1163–1176. [Google Scholar] [CrossRef] [PubMed]
- Li, D.; Fu, Z.; Chen, R.; Zhao, X.; Zhou, Y.; Zeng, B.; Yu, M.; Zhou, Q.; Lin, Q.; Gao, W.; et al. Inhibition of glutamine metabolism counteracts pancreatic cancer stem cell features and sensitizes cells to radiotherapy. Oncotarget 2015, 6, 31151–31163. [Google Scholar] [CrossRef] [PubMed]
- Peyraud, F.; Guegan, J.P.; Bodet, D.; Cousin, S.; Bessede, A.; Italiano, A. Targeting Tryptophan Catabolism in Cancer Immunotherapy Era: Challenges and Perspectives. Front. Immunol. 2022, 13, 807271. [Google Scholar] [CrossRef] [PubMed]
- Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 2016, 16, 582–598. [Google Scholar] [CrossRef]
- Munn, D.H.; Mellor, A.L. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol. 2013, 34, 137–143. [Google Scholar] [CrossRef]
- Mezrich, J.D.; Fechner, J.H.; Zhang, X.; Johnson, B.P.; Burlingham, W.J.; Bradfield, C.A. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J. Immunol. 2010, 185, 3190–3198. [Google Scholar] [CrossRef] [PubMed]
- Liu, Y.; Liang, X.; Dong, W.; Fang, Y.; Lv, J.; Zhang, T.; Fiskesund, R.; Xie, J.; Liu, J.; Yin, X.; et al. Tumor-Repopulating Cells Induce PD-1 Expression in CD8. Cancer Cell 2018, 33, 480–494.e487. [Google Scholar] [CrossRef] [PubMed]
- Nguyen, N.T.; Kimura, A.; Nakahama, T.; Chinen, I.; Masuda, K.; Nohara, K.; Fujii-Kuriyama, Y.; Kishimoto, T. Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc. Natl. Acad. Sci. USA 2010, 107, 19961–19966. [Google Scholar] [CrossRef] [PubMed]
- Sahu, D.; Gupta, S.; Hau, A.M.; Nakashima, K.; Leivo, M.Z.; Searles, S.C.; Elson, P.; Bomalaski, J.S.; Casteel, D.E.; Boss, G.R.; et al. Argininosuccinate Synthetase 1 Loss in Invasive Bladder Cancer Regulates Survival through General Control Nonderepressible 2 Kinase-Mediated Eukaryotic Initiation Factor 2α Activity and Is Targetable by Pegylated Arginine Deiminase. Am. J. Pathol. 2017, 187, 200–213. [Google Scholar] [CrossRef] [PubMed]
- Delage, B.; Luong, P.; Maharaj, L.; O’Riain, C.; Syed, N.; Crook, T.; Hatzimichael, E.; Papoudou-Bai, A.; Mitchell, T.J.; Whittaker, S.J.; et al. Promoter methylation of argininosuccinate synthetase-1 sensitises lymphomas to arginine deiminase treatment, autophagy and caspase-dependent apoptosis. Cell Death Dis. 2012, 3, e342. [Google Scholar] [CrossRef]
- Keshet, R.; Szlosarek, P.; Carracedo, A.; Erez, A. Rewiring urea cycle metabolism in cancer to support anabolism. Nat. Rev. Cancer 2018, 18, 634–645. [Google Scholar] [CrossRef] [PubMed]
- Albaugh, V.L.; Pinzon-Guzman, C.; Barbul, A. Arginine-Dual roles as an onconutrient and immunonutrient. J. Surg. Oncol. 2017, 115, 273–280. [Google Scholar] [CrossRef] [PubMed]
- Mazzone, M.; Menga, A.; Castegna, A. Metabolism and TAM functions-it takes two to tango. FEBS J. 2018, 285, 700–716. [Google Scholar] [CrossRef]
- Grzywa, T.M.; Sosnowska, A.; Matryba, P.; Rydzynska, Z.; Jasinski, M.; Nowis, D.; Golab, J. Myeloid Cell-Derived Arginase in Cancer Immune Response. Front. Immunol. 2020, 11, 938. [Google Scholar] [CrossRef] [PubMed]
- Rodríguez, P.C.; Ochoa, A.C. Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: Mechanisms and therapeutic perspectives. Immunol. Rev. 2008, 222, 180–191. [Google Scholar] [CrossRef] [PubMed]
- Martinez-Outschoorn, U.E.; Trimmer, C.; Lin, Z.; Whitaker-Menezes, D.; Chiavarina, B.; Zhou, J.; Wang, C.; Pavlides, S.; Martinez-Cantarin, M.P.; Capozza, F.; et al. Autophagy in cancer associated fibroblasts promotes tumor cell survival: Role of hypoxia, HIF1 induction and NFκB activation in the tumor stromal microenvironment. Cell Cycle 2010, 9, 3515–3533. [Google Scholar] [CrossRef] [PubMed]
- Marigo, I.; Dolcetti, L.; Serafini, P.; Zanovello, P.; Bronte, V. Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol. Rev. 2008, 222, 162–179. [Google Scholar] [CrossRef]
- Lemos, H.; Huang, L.; Prendergast, G.C.; Mellor, A.L. Immune control by amino acid catabolism during tumorigenesis and therapy. Nat. Rev. Cancer 2019, 19, 162–175. [Google Scholar] [CrossRef]
- Thomas, S.R.; Mohr, D.; Stocker, R. Nitric oxide inhibits indoleamine 2,3-dioxygenase activity in interferon-gamma primed mononuclear phagocytes. J. Biol. Chem. 1994, 269, 14457–14464. [Google Scholar] [CrossRef] [PubMed]
- Becker, J.C.; Andersen, M.H.; Schrama, D.; Thor Straten, P. Immune-suppressive properties of the tumor microenvironment. Cancer Immunol. Immunother. 2013, 62, 1137–1148. [Google Scholar] [CrossRef] [PubMed]
- Sahin, E.; Haubenwallner, S.; Kuttke, M.; Kollmann, I.; Halfmann, A.; Dohnal, A.M.; Chen, L.; Cheng, P.; Hoesel, B.; Einwallner, E.; et al. Macrophage PTEN regulates expression and secretion of arginase I modulating innate and adaptive immune responses. J. Immunol. 2014, 193, 1717–1727. [Google Scholar] [CrossRef]
- Rodriguez, P.C.; Quiceno, D.G.; Zabaleta, J.; Ortiz, B.; Zea, A.H.; Piazuelo, M.B.; Delgado, A.; Correa, P.; Brayer, J.; Sotomayor, E.M.; et al. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res. 2004, 64, 5839–5849. [Google Scholar] [CrossRef] [PubMed]
- Geiger, R.; Rieckmann, J.C.; Wolf, T.; Basso, C.; Feng, Y.; Fuhrer, T.; Kogadeeva, M.; Picotti, P.; Meissner, F.; Mann, M.; et al. L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity. Cell 2016, 167, 829–842.e813. [Google Scholar] [CrossRef] [PubMed]
- Lamas, B.; Vergnaud-Gauduchon, J.; Goncalves-Mendes, N.; Perche, O.; Rossary, A.; Vasson, M.P.; Farges, M.C. Altered functions of natural killer cells in response to L-Arginine availability. Cell Immunol. 2012, 280, 182–190. [Google Scholar] [CrossRef] [PubMed]
- Bader, J.E.; Voss, K.; Rathmell, J.C. Targeting Metabolism to Improve the Tumor Microenvironment for Cancer Immunotherapy. Mol. Cell 2020, 78, 1019–1033. [Google Scholar] [CrossRef]
- Sedillo, J.C.; Cryns, V.L. Targeting the methionine addiction of cancer. Am. J. Cancer Res. 2022, 12, 2249–2276. [Google Scholar] [PubMed]
- Wanders, D.; Hobson, K.; Ji, X. Methionine Restriction and Cancer Biology. Nutrients 2020, 12, 684. [Google Scholar] [CrossRef]
- Bian, Y.; Li, W.; Kremer, D.M.; Sajjakulnukit, P.; Li, S.; Crespo, J.; Nwosu, Z.C.; Zhang, L.; Czerwonka, A.; Pawłowska, A.; et al. Cancer SLC43A2 alters T cell methionine metabolism and histone methylation. Nature 2020, 585, 277–282. [Google Scholar] [CrossRef]
- Zhang, Y.; Yang, H.; Zhao, J.; Wan, P.; Hu, Y.; Lv, K.; Yang, X.; Ma, M. Activation of MAT2A-RIP1 signaling axis reprograms monocytes in gastric cancer. J. Immunother. Cancer 2021, 9, e001364. [Google Scholar] [CrossRef]
- Wei, Z.; Liu, X.; Cheng, C.; Yu, W.; Yi, P. Metabolism of Amino Acids in Cancer. Front. Cell Dev. Biol. 2020, 8, 603837. [Google Scholar] [CrossRef]
- Geeraerts, S.L.; Heylen, E.; De Keersmaecker, K.; Kampen, K.R. The ins and outs of serine and glycine metabolism in cancer. Nat. Metab. 2021, 3, 131–141. [Google Scholar] [CrossRef] [PubMed]
- Newman, A.C.; Maddocks, O.D.K. One-carbon metabolism in cancer. Br. J. Cancer 2017, 116, 1499–1504. [Google Scholar] [CrossRef] [PubMed]
- Fan, T.W.M.; Bruntz, R.C.; Yang, Y.; Song, H.; Chernyavskaya, Y.; Deng, P.; Zhang, Y.; Shah, P.P.; Beverly, L.J.; Qi, Z.; et al. synthesis of serine and glycine fuels purine nucleotide biosynthesis in human lung cancer tissues. J. Biol. Chem. 2019, 294, 13464–13477. [Google Scholar] [CrossRef] [PubMed]
- Tibbetts, A.S.; Appling, D.R. Compartmentalization of Mammalian folate-mediated one-carbon metabolism. Annu. Rev. Nutr. 2010, 30, 57–81. [Google Scholar] [CrossRef] [PubMed]
- Gao, X.; Lee, K.; Reid, M.A.; Sanderson, S.M.; Qiu, C.; Li, S.; Liu, J.; Locasale, J.W. Serine Availability Influences Mitochondrial Dynamics and Function through Lipid Metabolism. Cell Rep. 2018, 22, 3507–3520. [Google Scholar] [CrossRef]
- Ma, E.H.; Bantug, G.; Griss, T.; Condotta, S.; Johnson, R.M.; Samborska, B.; Mainolfi, N.; Suri, V.; Guak, H.; Balmer, M.L.; et al. Serine Is an Essential Metabolite for Effector T Cell Expansion. Cell Metab. 2017, 25, 345–357. [Google Scholar] [CrossRef] [PubMed]
- Goveia, J.; Pircher, A.; Conradi, L.C.; Kalucka, J.; Lagani, V.; Dewerchin, M.; Eelen, G.; DeBerardinis, R.J.; Wilson, I.D.; Carmeliet, P. Meta-analysis of clinical metabolic profiling studies in cancer: Challenges and opportunities. EMBO Mol. Med. 2016, 8, 1134–1142. [Google Scholar] [CrossRef] [PubMed]
- McCarty, M.F.; O’Keefe, J.H.; DiNicolantonio, J.J. Dietary Glycine Is Rate-Limiting for Glutathione Synthesis and May Have Broad Potential for Health Protection. Ochsner. J. 2018, 18, 81–87. [Google Scholar]
- Min, J.Y.; Chun, K.S.; Kim, D.H. The versatile utility of cysteine as a target for cancer treatment. Front. Oncol. 2022, 12, 997919. [Google Scholar] [CrossRef] [PubMed]
- Martínez-Reyes, I.; Chandel, N.S. Cancer metabolism: Looking forward. Nat. Rev. Cancer 2021, 21, 669–680. [Google Scholar] [CrossRef] [PubMed]
- Liu, X.; Nie, L.; Zhang, Y.; Yan, Y.; Wang, C.; Colic, M.; Olszewski, K.; Horbath, A.; Chen, X.; Lei, G.; et al. Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis. Nat. Cell Biol. 2023, 25, 404–414. [Google Scholar] [CrossRef]
- Srivastava, M.K.; Sinha, P.; Clements, V.K.; Rodriguez, P.; Ostrand-Rosenberg, S. Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res. 2010, 70, 68–77. [Google Scholar] [CrossRef]
- Yan, Z.; Garg, S.K.; Kipnis, J.; Banerjee, R. Extracellular redox modulation by regulatory T cells. Nat. Chem. Biol. 2009, 5, 721–723. [Google Scholar] [CrossRef]
- Wang, W.; Kryczek, I.; Dostál, L.; Lin, H.; Tan, L.; Zhao, L.; Lu, F.; Wei, S.; Maj, T.; Peng, D.; et al. Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer. Cell 2016, 165, 1092–1105. [Google Scholar] [CrossRef] [PubMed]
- Jin, G.; Hong, W.; Guo, Y.; Bai, Y.; Chen, B. Molecular Mechanism of Pancreatic Stellate Cells Activation in Chronic Pancreatitis and Pancreatic Cancer. J. Cancer 2020, 11, 1505–1515. [Google Scholar] [CrossRef] [PubMed]
- Sousa, C.M.; Biancur, D.E.; Wang, X.; Halbrook, C.J.; Sherman, M.H.; Zhang, L.; Kremer, D.; Hwang, R.F.; Witkiewicz, A.K.; Ying, H.; et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 2016, 536, 479–483. [Google Scholar] [CrossRef] [PubMed]
- Elia, I.; Rossi, M.; Stegen, S.; Broekaert, D.; Doglioni, G.; van Gorsel, M.; Boon, R.; Escalona-Noguero, C.; Torrekens, S.; Verfaillie, C.; et al. Breast cancer cells rely on environmental pyruvate to shape the metastatic niche. Nature 2019, 568, 117–121. [Google Scholar] [CrossRef] [PubMed]
- Ron-Harel, N.; Ghergurovich, J.M.; Notarangelo, G.; LaFleur, M.W.; Tsubosaka, Y.; Sharpe, A.H.; Rabinowitz, J.D.; Haigis, M.C. T Cell Activation Depends on Extracellular Alanine. Cell Rep. 2019, 28, 3011–3021.e3014. [Google Scholar] [CrossRef]
- Ohta, A. A Metabolic Immune Checkpoint: Adenosine in Tumor Microenvironment. Front. Immunol. 2016, 7, 109. [Google Scholar] [CrossRef] [PubMed]
- Sun, C.; Wang, B.; Hao, S. Adenosine-A2A Receptor Pathway in Cancer Immunotherapy. Front. Immunol. 2022, 13, 837230. [Google Scholar] [CrossRef]
- Blay, J.; White, T.D.; Hoskin, D.W. The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Cancer Res. 1997, 57, 2602–2605. [Google Scholar] [PubMed]
- Eltzschig, H.K.; Thompson, L.F.; Karhausen, J.; Cotta, R.J.; Ibla, J.C.; Robson, S.C.; Colgan, S.P. Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: Coordination by extracellular nucleotide metabolism. Blood 2004, 104, 3986–3992. [Google Scholar] [CrossRef] [PubMed]
- Augustin, R.C.; Leone, R.D.; Naing, A.; Fong, L.; Bao, R.; Luke, J.J. Next steps for clinical translation of adenosine pathway inhibition in cancer immunotherapy. J. Immunother. Cancer 2022, 10, e004089. [Google Scholar] [CrossRef]
- Ye, H.; Zhao, J.; Xu, X.; Zhang, D.; Shen, H.; Wang, S. Role of adenosine A2a receptor in cancers and autoimmune diseases. Immun. Inflamm. Dis. 2023, 11, e826. [Google Scholar] [CrossRef] [PubMed]
- Fredholm, B.B.; IJzerman, A.P.; Jacobson, K.A.; Klotz, K.N.; Linden, J. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol. Rev. 2001, 53, 527–552. [Google Scholar] [CrossRef] [PubMed]
- Mediavilla-Varela, M.; Luddy, K.; Noyes, D.; Khalil, F.K.; Neuger, A.M.; Soliman, H.; Antonia, S.J. Antagonism of adenosine A2A receptor expressed by lung adenocarcinoma tumor cells and cancer associated fibroblasts inhibits their growth. Cancer Biol. Ther. 2013, 14, 860–868. [Google Scholar] [CrossRef]
- Ma, X.L.; Shen, M.N.; Hu, B.; Wang, B.L.; Yang, W.J.; Lv, L.H.; Wang, H.; Zhou, Y.; Jin, A.L.; Sun, Y.F.; et al. CD73 promotes hepatocellular carcinoma progression and metastasis via activating PI3K/AKT signaling by inducing Rap1-mediated membrane localization of P110β and predicts poor prognosis. J. Hematol. Oncol. 2019, 12, 37. [Google Scholar] [CrossRef] [PubMed]
- Sitkovsky, M.V.; Lukashev, D.; Apasov, S.; Kojima, H.; Koshiba, M.; Caldwell, C.; Ohta, A.; Thiel, M. Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annu. Rev. Immunol. 2004, 22, 657–682. [Google Scholar] [CrossRef]
- Chang, C.H.; Pearce, E.L. Emerging concepts of T cell metabolism as a target of immunotherapy. Nat. Immunol. 2016, 17, 364–368. [Google Scholar] [CrossRef] [PubMed]
- Butler, J.J.; Mader, J.S.; Watson, C.L.; Zhang, H.; Blay, J.; Hoskin, D.W. Adenosine inhibits activation-induced T cell expression of CD2 and CD28 co-stimulatory molecules: Role of interleukin-2 and cyclic AMP signaling pathways. J. Cell Biochem. 2003, 89, 975–991. [Google Scholar] [CrossRef]
- Sorrentino, C.; Hossain, F.; Rodriguez, P.C.; Sierra, R.A.; Pannuti, A.; Osborne, B.A.; Minter, L.M.; Miele, L.; Morello, S. Adenosine A2A Receptor Stimulation Inhibits TCR-Induced Notch1 Activation in CD8+T-Cells. Front. Immunol. 2019, 10, 162. [Google Scholar] [CrossRef]
- Chambers, A.M.; Wang, J.; Lupo, K.B.; Yu, H.; Atallah Lanman, N.M.; Matosevic, S. Adenosinergic Signaling Alters Natural Killer Cell Functional Responses. Front. Immunol. 2018, 9, 2533. [Google Scholar] [CrossRef]
- Young, A.; Ngiow, S.F.; Gao, Y.; Patch, A.M.; Barkauskas, D.S.; Messaoudene, M.; Lin, G.; Coudert, J.D.; Stannard, K.A.; Zitvogel, L.; et al. A2AR Adenosine Signaling Suppresses Natural Killer Cell Maturation in the Tumor Microenvironment. Cancer Res. 2018, 78, 1003–1016. [Google Scholar] [CrossRef] [PubMed]
- Zarek, P.E.; Huang, C.T.; Lutz, E.R.; Kowalski, J.; Horton, M.R.; Linden, J.; Drake, C.G.; Powell, J.D. A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. Blood 2008, 111, 251–259. [Google Scholar] [CrossRef]
- Ohta, A.; Kini, R.; Subramanian, M.; Madasu, M.; Sitkovsky, M. The development and immunosuppressive functions of CD4+ CD25+ FoxP3+ regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway. Front. Immunol. 2012, 3, 190. [Google Scholar] [CrossRef]
- Li, J.; Wang, L.; Chen, X.; Li, L.; Li, Y.; Ping, Y.; Huang, L.; Yue, D.; Zhang, Z.; Wang, F.; et al. CD39/CD73 upregulation on myeloid-derived suppressor cells via TGF-β-mTOR-HIF-1 signaling in patients with non-small cell lung cancer. Oncoimmunology 2017, 6, e1320011. [Google Scholar] [CrossRef] [PubMed]
- Ryzhov, S.; Novitskiy, S.V.; Goldstein, A.E.; Biktasova, A.; Blackburn, M.R.; Biaggioni, I.; Dikov, M.M.; Feoktistov, I. Adenosinergic regulation of the expansion and immunosuppressive activity of CD11b+Gr1+ cells. J. Immunol. 2011, 187, 6120–6129. [Google Scholar] [CrossRef]
- Ferrante, C.J.; Pinhal-Enfield, G.; Elson, G.; Cronstein, B.N.; Hasko, G.; Outram, S.; Leibovich, S.J. The adenosine-dependent angiogenic switch of macrophages to an M2-like phenotype is independent of interleukin-4 receptor alpha (IL-4Rα) signaling. Inflammation 2013, 36, 921–931. [Google Scholar] [CrossRef]
- Novitskiy, S.V.; Ryzhov, S.; Zaynagetdinov, R.; Goldstein, A.E.; Huang, Y.; Tikhomirov, O.Y.; Blackburn, M.R.; Biaggioni, I.; Carbone, D.P.; Feoktistov, I.; et al. Adenosine receptors in regulation of dendritic cell differentiation and function. Blood 2008, 112, 1822–1831. [Google Scholar] [CrossRef]
- Kuo, C.C.; Wu, J.Y.; Wu, K.K. Cancer-derived extracellular succinate: A driver of cancer metastasis. J. Biomed. Sci. 2022, 29, 93. [Google Scholar] [CrossRef] [PubMed]
- Wu, J.Y.; Huang, T.W.; Hsieh, Y.T.; Wang, Y.F.; Yen, C.C.; Lee, G.L.; Yeh, C.C.; Peng, Y.J.; Kuo, Y.Y.; Wen, H.T.; et al. Cancer-Derived Succinate Promotes Macrophage Polarization and Cancer Metastasis via Succinate Receptor. Mol. Cell 2020, 77, 213–227.e215. [Google Scholar] [CrossRef] [PubMed]
- Prag, H.A.; Gruszczyk, A.V.; Huang, M.M.; Beach, T.E.; Young, T.; Tronci, L.; Nikitopoulou, E.; Mulvey, J.F.; Ascione, R.; Hadjihambi, A.; et al. Mechanism of succinate efflux upon reperfusion of the ischaemic heart. Cardiovasc. Res. 2021, 117, 1188–1201. [Google Scholar] [CrossRef]
- Laukka, T.; Mariani, C.J.; Ihantola, T.; Cao, J.Z.; Hokkanen, J.; Kaelin, W.G.; Godley, L.A.; Koivunen, P. Fumarate and Succinate Regulate Expression of Hypoxia-inducible Genes via TET Enzymes. J. Biol. Chem. 2016, 291, 4256–4265. [Google Scholar] [CrossRef] [PubMed]
- Xiao, M.; Yang, H.; Xu, W.; Ma, S.; Lin, H.; Zhu, H.; Liu, L.; Liu, Y.; Yang, C.; Xu, Y.; et al. Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes. Dev. 2012, 26, 1326–1338. [Google Scholar] [CrossRef] [PubMed]
- Gudgeon, N.; Munford, H.; Bishop, E.L.; Hill, J.; Fulton-Ward, T.; Bending, D.; Roberts, J.; Tennant, D.A.; Dimeloe, S. Succinate uptake by T cells suppresses their effector function via inhibition of mitochondrial glucose oxidation. Cell Rep. 2022, 40, 111193. [Google Scholar] [CrossRef] [PubMed]
- Sanchez, M.; Hamel, D.; Bajon, E.; Duhamel, F.; Bhosle, V.K.; Zhu, T.; Rivera, J.C.; Dabouz, R.; Nadeau-Vallée, M.; Sitaras, N.; et al. The Succinate Receptor SUCNR1 Resides at the Endoplasmic Reticulum and Relocates to the Plasma Membrane in Hypoxic Conditions. Cells 2022, 11, 2185. [Google Scholar] [CrossRef] [PubMed]
- Littlewood-Evans, A.; Sarret, S.; Apfel, V.; Loesle, P.; Dawson, J.; Zhang, J.; Muller, A.; Tigani, B.; Kneuer, R.; Patel, S.; et al. GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis. J. Exp. Med. 2016, 213, 1655–1662. [Google Scholar] [CrossRef]
- Mu, X.; Zhao, T.; Xu, C.; Shi, W.; Geng, B.; Shen, J.; Zhang, C.; Pan, J.; Yang, J.; Hu, S.; et al. Oncometabolite succinate promotes angiogenesis by upregulating VEGF expression through GPR91-mediated STAT3 and ERK activation. Oncotarget 2017, 8, 13174–13185. [Google Scholar] [CrossRef]
- Gilissen, J.; Jouret, F.; Pirotte, B.; Hanson, J. Insight into SUCNR1 (GPR91) structure and function. Pharmacol. Ther. 2016, 159, 56–65. [Google Scholar] [CrossRef]
- Vargas, S.L.; Toma, I.; Kang, J.J.; Meer, E.J.; Peti-Peterdi, J. Activation of the succinate receptor GPR91 in macula densa cells causes renin release. J. Am. Soc. Nephrol. 2009, 20, 1002–1011. [Google Scholar] [CrossRef] [PubMed]
- Geeraerts, X.; Bolli, E.; Fendt, S.M.; Van Ginderachter, J.A. Macrophage Metabolism As Therapeutic Target for Cancer, Atherosclerosis, and Obesity. Front. Immunol. 2017, 8, 289. [Google Scholar] [CrossRef]
- Lampropoulou, V.; Sergushichev, A.; Bambouskova, M.; Nair, S.; Vincent, E.E.; Loginicheva, E.; Cervantes-Barragan, L.; Ma, X.; Huang, S.C.; Griss, T.; et al. Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation. Cell Metab. 2016, 24, 158–166. [Google Scholar] [CrossRef] [PubMed]
- Weiss, J.M.; Davies, L.C.; Karwan, M.; Ileva, L.; Ozaki, M.K.; Cheng, R.Y.; Ridnour, L.A.; Annunziata, C.M.; Wink, D.A.; McVicar, D.W. Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors. J. Clin. Investig. 2018, 128, 3794–3805. [Google Scholar] [CrossRef] [PubMed]
- Kelly, B.; O’Neill, L.A. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res. 2015, 25, 771–784. [Google Scholar] [CrossRef]
- Parolini, I.; Federici, C.; Raggi, C.; Lugini, L.; Palleschi, S.; De Milito, A.; Coscia, C.; Iessi, E.; Logozzi, M.; Molinari, A.; et al. Microenvironmental pH is a key factor for exosome traffic in tumor cells. J. Biol. Chem. 2009, 284, 34211–34222. [Google Scholar] [CrossRef]
- Kowal, J.; Tkach, M.; Théry, C. Biogenesis and secretion of exosomes. Curr. Opin. Cell Biol. 2014, 29, 116–125. [Google Scholar] [CrossRef]
- Kosaka, N.; Kogure, A.; Yamamoto, T.; Urabe, F.; Usuba, W.; Prieto-Vila, M.; Ochiya, T. Exploiting the message from cancer: The diagnostic value of extracellular vesicles for clinical applications. Exp. Mol. Med. 2019, 51, 1–9. [Google Scholar] [CrossRef] [PubMed]
- Wang, W.; Zhu, N.; Yan, T.; Shi, Y.N.; Chen, J.; Zhang, C.J.; Xie, X.J.; Liao, D.F.; Qin, L. The crosstalk: Exosomes and lipid metabolism. Cell Commun. Signal. 2020, 18, 119. [Google Scholar] [CrossRef] [PubMed]
- Liu, Y.; Gu, Y.; Cao, X. The exosomes in tumor immunity. Oncoimmunology 2015, 4, e1027472. [Google Scholar] [CrossRef]
- Clayton, A.; Al-Taei, S.; Webber, J.; Mason, M.D.; Tabi, Z. Cancer exosomes express CD39 and CD73, which suppress T cells through adenosine production. J. Immunol. 2011, 187, 676–683. [Google Scholar] [CrossRef] [PubMed]
- Turiello, R.; Capone, M.; Morretta, E.; Monti, M.C.; Madonna, G.; Azzaro, R.; Del Gaudio, P.; Simeone, E.; Sorrentino, A.; Ascierto, P.A.; et al. Exosomal CD73 from serum of patients with melanoma suppresses lymphocyte functions and is associated with therapy resistance to anti-PD-1 agents. J. Immunother. Cancer 2022, 10, e004043. [Google Scholar] [CrossRef] [PubMed]
- Avellaneda Matteo, D.; Grunseth, A.J.; Gonzalez, E.R.; Anselmo, S.L.; Kennedy, M.A.; Moman, P.; Scott, D.A.; Hoang, A.; Sohl, C.D. Molecular mechanisms of isocitrate dehydrogenase 1 (IDH1) mutations identified in tumors: The role of size and hydrophobicity at residue 132 on catalytic efficiency. J. Biol. Chem. 2017, 292, 7971–7983. [Google Scholar] [CrossRef]
- Yang, H.; Xie, S.; Liang, B.; Tang, Q.; Liu, H.; Wang, D.; Huang, G. Exosomal IDH1 increases the resistance of colorectal cancer cells to 5-Fluorouracil. J. Cancer 2021, 12, 4862–4872. [Google Scholar] [CrossRef]
- Zhang, Q.; Yang, X.; Liu, H. Extracellular Vesicles in Cancer Metabolism: Implications for Cancer Diagnosis and Treatment. Technol. Cancer Res. Treat. 2021, 20, 15330338211037821. [Google Scholar] [CrossRef]
- Risha, Y.; Minic, Z.; Ghobadloo, S.M.; Berezovski, M.V. The proteomic analysis of breast cell line exosomes reveals disease patterns and potential biomarkers. Sci. Rep. 2020, 10, 13572. [Google Scholar] [CrossRef] [PubMed]
- Ronquist, K.G.; Sanchez, C.; Dubois, L.; Chioureas, D.; Fonseca, P.; Larsson, A.; Ullén, A.; Yachnin, J.; Ronquist, G.; Panaretakis, T. Energy-requiring uptake of prostasomes and PC3 cell-derived exosomes into non-malignant and malignant cells. J. Extracell. Vesicles 2016, 5, 29877. [Google Scholar] [CrossRef]
- Dai, J.; Escara-Wilke, J.; Keller, J.M.; Jung, Y.; Taichman, R.S.; Pienta, K.J.; Keller, E.T. Primary prostate cancer educates bone stroma through exosomal pyruvate kinase M2 to promote bone metastasis. J. Exp. Med. 2019, 216, 2883–2899. [Google Scholar] [CrossRef]
- Hou, P.P.; Luo, L.J.; Chen, H.Z.; Chen, Q.T.; Bian, X.L.; Wu, S.F.; Zhou, J.X.; Zhao, W.X.; Liu, J.M.; Wang, X.M.; et al. Ectosomal PKM2 Promotes HCC by Inducing Macrophage Differentiation and Remodeling the Tumor Microenvironment. Mol. Cell 2020, 78, 1192–1206.e1110. [Google Scholar] [CrossRef]
- Demory Beckler, M.; Higginbotham, J.N.; Franklin, J.L.; Ham, A.J.; Halvey, P.J.; Imasuen, I.E.; Whitwell, C.; Li, M.; Liebler, D.C.; Coffey, R.J. Proteomic analysis of exosomes from mutant KRAS colon cancer cells identifies intercellular transfer of mutant KRAS. Mol. Cell. Proteom. 2013, 12, 343–355. [Google Scholar] [CrossRef]
- Shen, R.K.; Zhu, X.; Yi, H.; Wu, C.Y.; Chen, F.; Dai, L.Q.; Lin, J.H. Proteomic identification of osteosarcoma-derived exosomes and their activation of pentose phosphate pathway. Int. J. Clin. Exp. Patho. 2016, 9, 4140–4148. [Google Scholar]
- Hu, X.; Ma, Z.; Xu, B.; Li, S.; Yao, Z.; Liang, B.; Wang, J.; Liao, W.; Lin, L.; Wang, C.; et al. Glutamine metabolic microenvironment drives M2 macrophage polarization to mediate trastuzumab resistance in HER2-positive gastric cancer. Cancer Commun. 2023, 43, 909–937. [Google Scholar] [CrossRef] [PubMed]
- Sosnowska, A.; Czystowska-Kuzmicz, M.; Golab, J. Extracellular vesicles released by ovarian carcinoma contain arginase 1 that mitigates antitumor immune response. Oncoimmunology 2019, 8, e1655370. [Google Scholar] [CrossRef] [PubMed]
- Puhka, M.; Takatalo, M.; Nordberg, M.E.; Valkonen, S.; Nandania, J.; Aatonen, M.; Yliperttula, M.; Laitinen, S.; Velagapudi, V.; Mirtti, T.; et al. Metabolomic Profiling of Extracellular Vesicles and Alternative Normalization Methods Reveal Enriched Metabolites and Strategies to Study Prostate Cancer-Related Changes. Theranostics 2017, 7, 3824–3841. [Google Scholar] [CrossRef]
- Wendler, F.; Favicchio, R.; Simon, T.; Alifrangis, C.; Stebbing, J.; Giamas, G. Extracellular vesicles swarm the cancer microenvironment: From tumor-stroma communication to drug intervention. Oncogene 2017, 36, 877–884. [Google Scholar] [CrossRef] [PubMed]
- Zhao, H.; Yang, L.; Baddour, J.; Achreja, A.; Bernard, V.; Moss, T.; Marini, J.C.; Tudawe, T.; Seviour, E.G.; San Lucas, F.A.; et al. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. eLife 2016, 5, e10250. [Google Scholar] [CrossRef] [PubMed]
- Tadokoro, H.; Hirayama, A.; Kudo, R.; Hasebe, M.; Yoshioka, Y.; Matsuzaki, J.; Yamamoto, Y.; Sugimoto, M.; Soga, T.; Ochiya, T. Adenosine leakage from perforin-burst extracellular vesicles inhibits perforin secretion by cytotoxic T-lymphocytes. PLoS ONE 2020, 15, e0231430. [Google Scholar] [CrossRef] [PubMed]
- Yin, X.; Zeng, W.; Wu, B.; Wang, L.; Wang, Z.; Tian, H.; Jiang, Y.; Clay, R.; Wei, X.; Qin, Y.; et al. PPARα Inhibition Overcomes Tumor-Derived Exosomal Lipid-Induced Dendritic Cell Dysfunction. Cell Rep. 2020, 33, 108278. [Google Scholar] [CrossRef] [PubMed]
- Snaebjornsson, M.T.; Janaki-Raman, S.; Schulze, A. Greasing the Wheels of the Cancer Machine: The Role of Lipid Metabolism in Cancer. Cell Metab. 2020, 31, 62–76. [Google Scholar] [CrossRef] [PubMed]
- Wang, D.; Dubois, R.N. Eicosanoids and cancer. Nat. Rev. Cancer 2010, 10, 181–193. [Google Scholar] [CrossRef]
- Ma, X.; Bi, E.; Lu, Y.; Su, P.; Huang, C.; Liu, L.; Wang, Q.; Yang, M.; Kalady, M.F.; Qian, J.; et al. Cholesterol Induces CD8. Cell Metab. 2019, 30, 143–156.e145. [Google Scholar] [CrossRef] [PubMed]
- Xu, S.; Chaudhary, O.; Rodríguez-Morales, P.; Sun, X.; Chen, D.; Zappasodi, R.; Xu, Z.; Pinto, A.F.M.; Williams, A.; Schulze, I.; et al. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8. Immunity 2021, 54, 1561–1577.e1567. [Google Scholar] [CrossRef]
- Bachem, A.; Makhlouf, C.; Binger, K.J.; de Souza, D.P.; Tull, D.; Hochheiser, K.; Whitney, P.G.; Fernandez-Ruiz, D.; Dähling, S.; Kastenmüller, W.; et al. Microbiota-Derived Short-Chain Fatty Acids Promote the Memory Potential of Antigen-Activated CD8. Immunity 2019, 51, 285–297.e285. [Google Scholar] [CrossRef]
- O’Sullivan, D.; Pearce, E.L. Fatty acid synthesis tips the TH17-Treg cell balance. Nat. Med. 2014, 20, 1235–1236. [Google Scholar] [CrossRef] [PubMed]
- Herber, D.L.; Cao, W.; Nefedova, Y.; Novitskiy, S.V.; Nagaraj, S.; Tyurin, V.A.; Corzo, A.; Cho, H.I.; Celis, E.; Lennox, B.; et al. Lipid accumulation and dendritic cell dysfunction in cancer. Nat. Med. 2010, 16, 880–886. [Google Scholar] [CrossRef]
- Dong, H.; Bullock, T.N. Metabolic influences that regulate dendritic cell function in tumors. Front. Immunol. 2014, 5, 24. [Google Scholar] [CrossRef] [PubMed]
- Su, P.; Wang, Q.; Bi, E.; Ma, X.; Liu, L.; Yang, M.; Qian, J.; Yi, Q. Enhanced Lipid Accumulation and Metabolism Are Required for the Differentiation and Activation of Tumor-Associated Macrophages. Cancer Res. 2020, 80, 1438–1450. [Google Scholar] [CrossRef] [PubMed]
- Kobayashi, T.; Lam, P.Y.; Jiang, H.; Bednarska, K.; Gloury, R.; Murigneux, V.; Tay, J.; Jacquelot, N.; Li, R.; Tuong, Z.K.; et al. Increased lipid metabolism impairs NK cell function and mediates adaptation to the lymphoma environment. Blood 2020, 136, 3004–3017. [Google Scholar] [CrossRef] [PubMed]
- Hossain, F.; Al-Khami, A.A.; Wyczechowska, D.; Hernandez, C.; Zheng, L.; Reiss, K.; Valle, L.D.; Trillo-Tinoco, J.; Maj, T.; Zou, W.; et al. Inhibition of Fatty Acid Oxidation Modulates Immunosuppressive Functions of Myeloid-Derived Suppressor Cells and Enhances Cancer Therapies. Cancer Immunol. Res. 2015, 3, 1236–1247. [Google Scholar] [CrossRef]
- Yan, D.; Yang, Q.; Shi, M.; Zhong, L.; Wu, C.; Meng, T.; Yin, H.; Zhou, J. Polyunsaturated fatty acids promote the expansion of myeloid-derived suppressor cells by activating the JAK/STAT3 pathway. Eur. J. Immunol. 2013, 43, 2943–2955. [Google Scholar] [CrossRef] [PubMed]
- Yasumoto, Y.; Miyazaki, H.; Vaidyan, L.K.; Kagawa, Y.; Ebrahimi, M.; Yamamoto, Y.; Ogata, M.; Katsuyama, Y.; Sadahiro, H.; Suzuki, M.; et al. Inhibition of Fatty Acid Synthase Decreases Expression of Stemness Markers in Glioma Stem Cells. PLoS ONE 2016, 11, e0147717. [Google Scholar] [CrossRef]
- Samudio, I.; Harmancey, R.; Fiegl, M.; Kantarjian, H.; Konopleva, M.; Korchin, B.; Kaluarachchi, K.; Bornmann, W.; Duvvuri, S.; Taegtmeyer, H.; et al. Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J. Clin. Investig. 2010, 120, 142–156. [Google Scholar] [CrossRef]
- Thornalley, P.J.; Langborg, A.; Minhas, H.S. Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose. Biochem. J. 1999, 344 Pt 1, 109–116. [Google Scholar] [CrossRef] [PubMed]
- Sousa Silva, M.; Gomes, R.A.; Ferreira, A.E.; Ponces Freire, A.; Cordeiro, C. The glyoxalase pathway: The first hundred years... and beyond. Biochem. J. 2013, 453, 1–15. [Google Scholar] [CrossRef] [PubMed]
- Al-Khami, A.A.; Rodriguez, P.C.; Ochoa, A.C. Metabolic reprogramming of myeloid-derived suppressor cells (MDSC) in cancer. Oncoimmunology 2016, 5, e1200771. [Google Scholar] [CrossRef] [PubMed]
- Baumann, T.; Dunkel, A.; Schmid, C.; Schmitt, S.; Hiltensperger, M.; Lohr, K.; Laketa, V.; Donakonda, S.; Ahting, U.; Lorenz-Depiereux, B.; et al. Regulatory myeloid cells paralyze T cells through cell-cell transfer of the metabolite methylglyoxal. Nat. Immunol. 2020, 21, 555–566. [Google Scholar] [CrossRef] [PubMed]
Metabolite | Cancer Cell | Teff and Tmem Cells | NK Cell | Treg | TAM | DC | CAF | MDSC |
---|---|---|---|---|---|---|---|---|
Adenosine | Express surface CD39 and CD73 to produce extracellular adenosine from adenine nucleotides [129,130]. A2AR activation supports cell growth [133]. | A2AR activation on CD4+ T cell inhibits IL-2 production, blocks upregulation of CD2 and CD28 [137]. A2AR activation inhibits TCR-Notch signaling, reduced IFNγ and Granzyme B production in CD8+ T cells [138]. | A2AR activation inhibits maturation of NK cell [140]. A2AR activation downregulates OXPHOS, glycolysis [139]. | Express surface CD39 and CD73 to produce extracellular adenosine from adenine nucleotides [129,130]. A2AR activation expands Treg population and increases CTLA-4 expression [142]. | A2AR activation induces M2 TAM polarization [145]. | A2AR activation inhibits antigen presentation [146]. | A2AR activation supports cell growth [133]. | MDSCs express surface CD39 and CD73 to produce extracellular adenosine from adenine nucleotides [143]. A2AR signaling promotes the generation of MDSCs [144]. |
Alanine | PDAC cells take up alanine from stellate cells and convert it to pyruvate to utilize it for TCA cycle [123]. Alanine-derived aKG is required for collagen hydroxylation in pre-metastatic niche tissue in breast cancer [124]. | Extracellular alanine required for T cell activation. T cells upregulate alanine import rather than depending on synthesis from pyruvate. Alanine is directed towards protein synthesis. Alanine deprivation causes failure to leave quiescence [125]. Reactivation of Tmem cells requires extracellular alanine [125]. | - - - | - - - | - - - | - - - | PDAC stellate cells upregulate autophagy to secrete alanine to cancer cells [123]. | - - - |
Arginine and Polyamines | ASS1 deficiency causes dependence on extracellular arginine, causing depletion from the TME [87]. Take up exogenous arginine for polyamine synthesis and nitric oxide production [88]. | Depletion of arginine from TME impairs Teff function [91,96]. Arginine depletion from TME inhibits Teff mTORC1 activity, decreases effector functions and promotes memory phenotype [94,100]. | Arginine depletion inhibits cytotoxicity, IFN-g production, and viability of NK cells [101]. | IDO expression depletes arginine from TME, which inhibits Teff and promotes Treg [96]. | M2 TAMs increase expression and secretion of Arg1 and deplete arginine from the TME to inhibit effector T cells [97]. TGFb signaling and HIF-1a-induced metabolic reprogramming upregulate arginine metabolism [45,93]. M2 TAMs secrete polyamines to promote cell division in cancer cells [45]. | IDO expression depletes arginine from TME, which inhibits Teff and promotes Treg [96]. | TGFb signaling and HIF-1a-induced metabolic reprogramming upregulate arginine metabolism [45,93]. IDO expression depletes arginine from TME, which inhibits Teff and promotes Treg [96]. | Secrete Arg1 into TME to deplete arginine and inhibit T cell anti-tumor function [99]. Arginine depletion upregulates expression of VISTA, CD39L1 immunosuppressive molecules [102]. |
Cysteine | Cancer cells upregulate cystine/glutamate antiporter xCT to resist ferroptosis, which depletes cysteine from the TME as a result [118]. Deplete cysteine from TME, which limits TIL activation and effector function [117]. | Naïve T cells rely on cysteine secreted from macrophages and DCs and take up cysteine via the neutral amino acid transporter ASC rather than importing cystine via xCT [119]. TIL activation and effector function is hampered by cysteine depletion by cancer cells and MDSCs [117]. | - - - | Inhibit extracellular DC-mediated cysteine production from GSH in order to inhibit Teff function [120]. | Secrete cysteine for utilization by naïve T cells [119]. | Supply cysteine for utilization by naïve T cells by secreting GSH, which is cleaved into cysteine in the extracellular space [119,120]. | Stromal cells upregulate xCT to produce excess GSH, which is transferred to cancer cells and promotes chemoresistance [202]. | Deplete cysteine from TME, which limits TIL activation and effector function [117]. |
Exosomes | Upregulate tumor-derived exosome (TDE) production in response to low pH and activation of HIF-1a/Rab27a [163,164]. TDE-associated CD39 and CD73 account for as much as 20% of extracellular ATP hydrolysis and adenosine production [168]. TDE from 5-fluorouracil (5FU)-resistant cancer cells transmitted isocitrate dehydrogenase (IDH1) to non-resistant cells, which induced 5FU resistance through increased NADPH production [171]. Several metabolic enzymes have been identified in TDEs including glycolytic, pentose phosphate pathway, and glutaminolytic enzymes [106,173,174,175,176,177,178,179,180]. Melanoma TDE sensitize pre-metastatic niche sites in lung epithelia by inhibiting the enzyme CH25H from producing 25-hydroxycholesterol (25HC) and inducing degradation of IFNg receptor IFNAR1 [203]. | Tumor-derived exosomes (TDEs) express Fas ligand and deliver to T cells to induce apoptosis [204]. TDE express TGFb, which inhibits CD25 (IL-2 receptor)-induced cell growth and cytolytic function in T cells and suppresses their activation by downregulating the expression of the TGFb receptor NKG2D [168,205]. TDE-associated adenosine inhibits T cell proliferation, inflammatory cytokine production, and perforin release [169,184]. TDE-associated arginase 1 (Arg1) depleted arginine from the TME, starving T cells and inhibiting their anti-tumor functions [94]. | Tumor-derived exosomes (TDEs) express TGFb, which suppresses NK cell activation by downregulating the expression of the TGFb receptor NKG2D [168]. | Tumor-derived exosomes (TDE) express TGFb, which activates and expands Treg cells [168]. | TAM-derived exosomes deliver lncRNA HISLA to cancer cells, which stabilizes HIF-1a expression, upregulates glycolysis and lactate production, and promotes chemoresistance in cancer cells [206]. TDEs condition tissue resident macrophages in pre-metastatic site by activating TLR2-NFkB signaling, which upregulates Arg1 and VEGF, increases NOS expression, inhibits OXPHOS, and increases glycolysis and lactate production [207]. | Tumor-infiltrating DCs take up long chain fatty acids from TDEs, which activated PPARa and FAO leading to inhibition of DC antigen presentation, failure to activate CD8+ T cells, and induction of Treg cells [185]. | Tumor-derived exosomes (TDEs) express TGFb, which transforms normal fibroblasts to cancer-associated fibroblasts (CAFs) [208]. TDE deliver miR-105 to reprogram CAF glucose and glutamine metabolism towards a catabolic phenotype to feed adjacent cancer cells and to detoxify TME waste [209]. CAF-derived exosomes are enriched in several glycolytic intermediates, TCA metabolites, amino acids, and lipids, and deliver these metabolites to cancer cells where they inhibit OXPHOS and increase glycolysis and glutaminolysis [183]. | - - - |
Glucose | Third highest consumer of glucose in the tumor [4]. Perform aerobic glycolysis where glucose metabolism is decoupled from mitochondrial metabolism and is instead converted to lactate [2]. Glucose is often depleted from poorly vascularized regions of the tumor [7]. High glycolytic flux promotes G-CSF secretion and recruitment of MDSCs [12]. | Second highest consumer of glucose in the tumor [4]. Perform aerobic glycolysis where glucose metabolism is decoupled from mitochondrial metabolism and is instead converted to lactate [3]. Glucose limitation blocks effector cytokine production [9]. | Uneducated NK cells mainly use OXPHOS for energy production. Educated NK cells upregulate glycolysis in addition to OXPHOS for energy production and cytotoxic functions [210]. | Low glucose induces FoxP3 expression, which converts anti-tumor CD4+ Teff cells into pro-tumor Treg cells [10]. Treg growth and suppressive function is inhibited by high glucose [11]. | M1 TAMs upregulate aerobic glycolysis in response to the harsh TME environment [211]. M2 TAMs further upregulate glycolysis and lactate production [159]. | Activated DCs upregulate glycolysis and lactate production [55]. | Hyperglycemia activates PDAC stellate cell CXCL12 production, binds CXCR4 receptor on cancer cell to activate MAPK and induces proliferation and migration [13]. | Highest consumer of glucose in the tumor [4]. |
Glutamine | Highest consumer of glutamine in the tumor [4]. Glutamine becomes conditionally essential to many cancers [60]. Glutaminolysis regulates mTOR signaling, redox balance, autophagy, apoptosis and ferroptosis [64,65,66,67]. | Teff cells increase glutaminolysis to support the TCA cycle and biosynthesis of cellular components [212]. | Require sustained glutaminolysis to maintain Myc expression [75]. | Treg differentiation by FoxP3 is inhibited by glutaminolysis [74]. | M1 TAMs have a truncated TCA cycle due to inactivation of IDH and SDH, and require glutamine as an alternative carbon source [213]. M1 TAMs require glutaminolysis for cytokine production, antigen presentation, and phagocytosis [72]. M2 TAMs upregulate glutaminolysis to produce excess alpha-ketoglutarate to reinforce M2 polarization through epigenetic reprogramming [73]. | Glutaminolysis maintains redox metabolism and supports DC activation and antigen presentation [78]. | CAFs produce and secrete excess glutamine from branched chain amino acids and aspartate for use by cancer cells [70]. | Increased glutamine consumption in tumor cells increases expression of LAP and CSF3, which promotes recruitment and generation of MDSCs [71]. |
Lactate | Many cancer types consume lactate as fuel when glucose is low [20,21]. Exogenous lactate acts in a paracrine fashion on neighboring cancer cells to stabilize HIF-1a/2a, activate c-Myc, and upregulate glutaminolysis [28,29]. | CD8+ T cells can consume lactate as fuel when glucose is low [23]. High extracellular lactate disrupts T cell glycolysis and mitochondrial metabolism and causes a net influx of lactate that lowers intracellular pH [33,34,35]. High extracellular lactate induces apoptosis in T and NK cells, limits effector functions and inhibits NFAT-mediated expression of proinflammatory cytokines [35,38]. High lactate disrupts chemotaxis and migration of CD4+ and CD8+ T cells and limits CD8+ release of perforin and granzyme [39]. | High extracellular lactate induces apoptosis in T and NK cells, limits effector functions and inhibits NFAT-mediated expression of proinflammatory cytokines [35,38]. | High lactate in the TME induces a switch from glycolysis to OXPHOS, which maintains Treg immunosuppressive function by allowing them to consume lactate [11]. The Treg transcription factor FoxP3 supports growth under low glucose high lactate environments by transcriptionally repressing Myc, suppressing glycolysis, increasing the rate of OXPHOS, and reversing the reaction catalyzed by LDH to consume lactate and recycle and maintain a pool of NAD+ [40]. Lactate induces Treg PD-1 expression through the transcription factor NFAT [43]. | High lactate in TME drives M2 TAM polarization by stabilizing HIF-1a expression, which induces M2 gene expression and polarization and promotes a switch from glycolytic metabolism to OXPHOS via lactic acid and lipid oxidation [45]. Lactate-HIF-1a signaling in TAMs drives significant VEGF expression and promotes vascularization of the tumor [45]. Lactylation modification of histones converts TAMs from the M1 to M2 phenotype [46]. Lactate inhibits expression of ATP6V0d2, preventing the degradation of HIF-2a in lysosomes and maintaining M2 HIF functions [47]. Lactate increases PD-L1 expression on TAM [48]. | High extracellular lactate prevents the diffusion of glycolytic pyruvate, and this accumulated lactate shifts the DC into a tolerogenic phenotype upon TLR stimulation [57]. | CAF respond to tumor-derived proinflammatory cytokines by producing and secreting lactate into the TME [49]. CAF upregulation of glycolytic lactate secretion can occur through hypoxia-induced expression of glycolytic genes via HIF-1a [49]. Cell-cell contacts with cancer cells activates SIRT3 ROS signaling in CAFs that upregulates MCT4 lactate export [49,50,51]. | Lactate receptor GPR81 activates MDSCs and generates resistance to radiotherapy by signaling through mTOR, HIF-1a and STAT3 [59]. |
Lipids | The signaling lipid prostaglandin E2 (PGE2) is the most abundant prostaglandin found in tumors [187]. PGE2 is produced by the enzyme COX2 in cancer cells and stromal cells and promotes inflammation and tumor growth by signaling through several signaling pathways (Ras, Erk, GSK3b, b-Catenin, and PPARd) in an autocrine and paracrine fashion [214,215,216,217]. | Lipid accumulation triggers FAO and OXPHOS, which induces a stronger memory phenotype and greater reactivation of T cells [190]. Cholesterol originating in the TME can accumulate in T cells, causing ER stress and blocking the synthesis and secretion of effector cytokines. This ER stress activates the unfolded protein response (UPR) pathway XBP-1, which also promotes the expression of immunosuppressive molecules like PD-1, TIM-3, and LAG-3, which hampers the anti-tumor immune response and promotes T cell dysfunction and exhaustion [188,189]. | Excess lipid metabolism induced NK cell mitochondrial dysfunction, suppressed cellular metabolism, and diminished IFN-g production and anti-tumor effector response [195]. | Lipid accumulation triggers FAO and OXPHOS, which generates more Treg cells than in tumors that contain fewer lipids [191]. | Enhanced lipid accumulation and metabolism drive M2 TAM differentiation and activation through mitochondrial ROS-induced JAK1-STAT6 signaling [194]. | Upregulation of CD204 in DC causes an increase in uptake of extracellular lipids, which hampers antigen processing and presentation [192]. TDE deliver lipids from cancer cells to DC, causing lipid accumulation, activation of PPARa, excess lipid droplet biogenesis, FAO, and shifts the metabolism of the DC to OXPHOS, which causes immune dysfunction [185]. | PGE2 is produced by the enzyme COX2 in cancer cells and stromal cells and promotes inflammation and tumor growth by signaling through one of several signaling pathways in an autocrine and paracrine fashion [218,219]. | Tumor MDSCs show increased FA uptake, storage, and oxidation compared to peripheral MDSCs [196]. PUFA activate JAK-STAT3 signaling to drive MDSC accumulation and immunoinhibitory function [197]. |
Methionine | Many cancers are addicted to methionine, and cancer cells maximize their methionine uptake by upregulating the methionine transporter SLC43A2 in addition to increasing production from their endogenous methionine cycle [103,104,105]. | Methionine addiction by cancer cells limits its availability for T cells in the tumor, resulting in low S-adenosylmethionine (SAM) production and the loss of dimethylation at histone H3K79me2. This alters epigenetic control and in turn blocks T cell immunity by reducing expression of STAT5-derived cytokines [105]. | - - - | - - - | - - - | - - - | - - - | - - - |
Methylglyoxal | - - - | Methylglyoxal acquired from MDSCs suppresses the metabolic changes that normally occur upon TCR activation including increased glucose uptake, glycolysis, and OXPHOS [201]. Methylglyoxal reacts with and depletes arginine from the T cell, which inhibits TCR signaling and T cell activation and abolishes TNFa, IFNg, and granzyme B production [201]. | - - - | - - - | - - - | - - - | - - - | MDSCs generate methylglyoxal as a by-product of glucose metabolism, and its accumulation suppresses glycolysis in MDSCs [198,199,200]. MDSCs directly contact and perform cell-to-cell transfer of methylglyoxal into CD8+ T cells [201]. |
Succinate | Succinate accumulates extracellularly in many cancers due to mitochondrial metabolic dysfunction, succinate dehydrogenase (SDH) mutations, and secretion from cancer cells by MCT-1 [147,148,149]. Succinate promotes cancer cell migration, EMT, invasion and metastasis, and angiogenesis [154]. Succinate activates the succinate receptors GPR91 and SUCNR1 on tumor cells [148]. SUCNR1 activation triggers extracellular succinate uptake and activates several downstream signaling pathways including Erk1/2, prostaglandin E2 (PGE2), p38 MAPK, Akt, and AMPK with various effects [147,154,155,157,158]. Succinate accumulation directly inhibits PHD and stabilizes HIF-1a expression [150]. High intracellular succinate disrupts the nuclear aKG/succinate ratio, which inhibits TET family DNA demethylases [97,151,152]. | Succinate is taken up by MCT-1 in CD4+ and CD8+ T cells, and this accumulated succinate blocks metabolic flux through the TCA cycle by inhibiting the enzyme succinyl CoA synthetase (SUCLA2) [153]. High succinate inhibits TIL anti-tumor activity by reducing INFg and TNFa production and degranulation [153]. CD4+ and CD8+ T cells downregulate SUCNR1 in response to succinate exposure [153]. | - - - | - - - | Activation of SUCNR1 on TAMs activates PI3K signaling and HIF-1a activation, triggering M2 TAM polarization and leading to immune suppression and cancer and TAM cell migration [147,148]. | - - - | Stromal cell activation of SUCNR1 upregulates VEGF production through STAT3 and Erk1/2 signaling to increase vascularization of the tumor [156]. | - - - |
Tryptophan | Exogenous tryptophan is required to maintain kynurenine pathway, NAD+ synthesis [79]. Express IDO to deplete extracellular tryptophan and inhibit T cell proliferation [81]. | Tryptophan depletion in the TME starves TILs, which induces GCN2 activation and mTOR inhibition and leads to anergy and cell cycle arrest [81]. Kynurenine produced from tryptophan activates the AhR receptor in CD4+ T cells, which causes them to differentiate into Tregs [81,82]. Kynurenine induces PD-1 expression on CD8+ T cells [83]. | - - - | Express IDO to deplete extracellular tryptophan, which inhibits Teff function and promotes Tregs [96]. | - - - | Express IDO to deplete extracellular tryptophan, which inhibits Teff function and promotes Tregs [96]. | Express IDO to deplete extracellular tryptophan, which inhibits Teff function and promotes Tregs [96]. | - - - |
Metabolic Pathway | Trial ID | Drug/Treatment | Target and Impact on TME | Cancer Type | Phase | Status |
---|---|---|---|---|---|---|
GLUCOSE | NCT05957939 | Alkaline glucosodienes | Block glycolysis, raise pH | Triple-negative breast cancer | Phase I | Not yet recruiting |
NCT01935531 | Diclofenac | Inhibit MYC, glycolysis, and lactate transport; lower lactate levels | Actinic keratosis | Phase I | Completed | |
NCT04114136 | Metformin, Rosiglitazone + anti-PD-1/PD-L1 mAB | Block glucose metabolism, sensitize to anti-PD-1 mAB | Multiple solid tumors | Phase II | Recruiting | |
NCT04542291 | Dapagliflozin | Sodium-glucose cotransporter-2 (SGLT2) | Pancreatic cancer | Phase I | Completed | |
NCT01205672 | Metformin | Glucose metabolism, mTOR | Endometrial cancer | Phase I | Completed | |
NCT03763396 | Ketoconazole, Posaconazole | Hexokinase 2, glucose metabolism | Glioma | Phase I | Not yet recruiting | |
NCT01620593 | Metformin, castration | Inhibit glucose metabolism | Prostate cancer | Phase II | Completed | |
GLUTAMINE | NCT02071888 | Telaglenastat | Glutaminase inhibitor | Hematological Tumors | Phase I | Completed |
NCT02071862 | Telaglenastat | Glutaminase inhibitor | Multiple solid tumors | Phase I | Completed | |
NCT02071927 | Telaglenastat | Glutaminase inhibitor | Leukemia | Phase I | Completed | |
NCT03872427 | Telaglenastat | Glutaminase inhibitor | Multiple solid tumors | Phase II | Active, not recruiting | |
NCT04250545 | Telaglenastat plus Sapanisertib | Glutaminase, mTOR | Squamous cell lung cancer, non-small cell lung cancer | Phase I | Active, not recruiting | |
NCT03528642 | Telaglenastat plus radiation and Temozolomide | Glutaminase, DNA replication | IDH-Mutated Diffuse Astrocytoma or Anaplastic Astrocytoma | Phase I | Active, not recruiting | |
NCT03831932 | Telaglenastat and Osimertinib | Glutaminase, EGFR | EGFR-mutated stage IV non-small cell lung cancer | Phase I/II | Active, not recruiting | |
NCT03428217 | Telaglenastat plus Cabozantinib | Glutaminase, VEGF | Renal cell carcinoma | Phase II | Completed | |
NCT03057600 | Telaglenastat plus Paclitaxel | Glutaminase, mitosis | Triple-negative breast cancer | Phase II | Completed | |
NCT03163667 | Telaglenastat plus Everolimus | Glutaminase, mTOR | Renal cell carcinoma | Phase II | Completed | |
NCT04471415 | DRP-104 | Glutamine metabolism | Non-small cell lung cancer | Phase I/II | Terminated | |
NCT06027086 | DRP-104 plus Durvalumab | Glutamine metabolism, enhance anti-PD-L1 therapy | Fibrolamellar Carcinoma | Phase Ib/II | Recruiting | |
ASPARAGINE | NCT01523808 | L-Asparaginase-erythrocyte suspension | Asparagine metabolism | Pancreatic adenocarcinoma | Phase I | Completed |
NCT03674242 | Eryaspase (L-Asparaginase-erythrocyte suspension) plus Gemcitabine and Carboplatin | Asparagine metabolism, DNA replication | Triple-negative breast cancer | Phase II/III | Terminated | |
NCT01523782 | GRASPA (L-Asparaginase-erythrocyte suspension) | Asparagine metabolism | Acute Lymphoblastic Leukemia | Phase II | Completed | |
NCT01810705 | GRASPA (L-Asparaginase-erythrocyte suspension) plus cytarabine | Asparagine metabolism, DNA replication | Acute Lymphoblastic Leukemia | Phase II | Completed | |
NCT01251809 | Oncaspar and Pegaspargase (pegylated recombinant asparaginase) | Asparagine metabolism | Acute Lymphoblastic Leukemia | Phase I/II | Terminated | |
NCT04953780 | Calaspargase pegol-mknl (pegylated recombinant asparaginase) plus cytarabine and idarubicin | Asparagine metabolism, DNA replication | Acute Myeloid Leukemia | Phase I | Active, not recruiting | |
ARGININE | NCT05759923 | OATD-02 | Arginase 1/2 inhibitor | Multiple solid tumors | Phase I | Recruiting |
NCT03236935 | NG-monomethyl-L-arginine (L-NMMA) and pembrolizumab | Nitric oxide synthase inhibitor, anti-PD-1 | Multiple solid tumors | Phase I | Active, not recruiting | |
NCT02285101 | PEG-BCT-100 (pegylated arginase) | Arginine metabolism | Melanoma | Phase I | Completed | |
NCT00988195 | PEG-BCT-100 (pegylated arginase) | Arginine metabolism | Hepatocellular carcinoma | Phase I | Completed | |
NCT03455140 | PEG-BCT-100 (pegylated arginase) | Arginine metabolism | Multiple solid and liquid tumors | Phase I/II | Completed | |
NCT01092091 | PEG-BCT-100 (pegylated arginase) | Arginine metabolism | Hepatocellular carcinoma | Phase II | Completed | |
NCT00029900 | ADI-PEG (pegylated arginine deiminase) | Arginine metabolism | Metastatic melanoma | Phase I | Completed | |
NCT01266018 | ADI-PEG 20 (pegylated arginine deiminase) | Arginine metabolism | Small cell lung cancer | Phase II | Terminated | |
NCT01497925 | ADI-PEG 20 (pegylated arginine deiminase) plus Docetaxel | Arginine metabolism, DNA replication | Prostate cancer, non-small cell lung cancer | Phase I | Completed | |
NCT02102022 | ADI-PEG 20 (pegylated arginine deiminase) plus FOLFOX | Arginine metabolism, DNA replication | Hepatocellular carcinoma | Phase I/II | Terminated | |
NCT01665183 | ADI-PEG 20 (pegylated arginine deiminase) plus Cisplatin | Arginine metabolism, DNA replication | Metastatic melanoma | Phase I | Completed | |
NCT03254732 | ADI-PEG 20 (pegylated arginine deiminase) plus Pembrolizumab | Arginine metabolism, anti-PD-1 | Multiple solid tumors | Phase Ib | Terminated | |
NCT01948843 | ADI-PEG 20 (pegylated arginine deiminase) plus Doxorubicin | Arginine metabolism, DNA repair | HER2 negative metastatic breast cancer | Phase I | Completed | |
NCT06085729 | ADI-PEG 20 (pegylated arginine deiminase) plus Carboplatin and Cabazitaxel | Arginine metabolism, DNA replication | Prostate cancer | Phase I/II | Recruiting | |
NCT02029690 | ADI-PEG 20 (pegylated arginine deiminase) plus Pemetrexed and Cisplatin | Arginine metabolism, folate metabolism, DNA replication | Multiple solid tumors | Phase I | Terminated | |
NCT03922880 | ADI-PEG 20 (pegylated arginine deiminase) plus Nivolumab and Ipilimumab | Arginine metabolism, anti-PD-1, anti-CTLA-4 | Uveal melanoma | Phase I | Completed | |
NCT02101593 | ADI-PEG 20 (pegylated arginine deiminase) plus Sorafenib | Arginine metabolism, cell signaling | Hepatocellular carcinoma | Phase I | Completed | |
NCT05001828 | ADI-PEG 20 (pegylated arginine deiminase) plus Venetoclax and Azacitidine | Arginine metabolism, BCL-2 inhibition, DNA replication | Acute myeloid leukemia | Phase I | Recruiting | |
NCT02101580 | ADI-PEG 20 (pegylated arginine deiminase) plus Nab-Paclitaxel and Gemcitabine | Arginine metabolism, DNA replication | Pancreatic cancer | Phase Ib | Completed | |
NCT05616624 | ADI-PEG 20 (pegylated arginine deiminase) plus Gemcitabine and Docetaxel | Arginine metabolism, DNA replication | Small cell lung cancer, non-small cell lung cancer | Phase I/II | Recruiting | |
NCT00520299 | ADI-PEG 20 (pegylated arginine deiminase) | Arginine metabolism | Melanoma | Phase I/II | Completed | |
NCT05813327 | ADI-PEG 20 (pegylated arginine deiminase) plus Ifosfamide and radiotherapy | Arginine metabolism, DNA replication | Sarcoma | Phase I/II | Recruiting | |
NCT03449901 | ADI-PEG 20 (pegylated arginine deiminase) plus Gemcitabine and Docetaxel | Arginine metabolism, DNA replication | Sarcomas, small cell lung cancer | Phase II | Completed | |
NCT00056992 | ADI-PEG 20 (pegylated arginine deiminase) | Arginine metabolism | Hepatocellular carcinoma | Phase II | Completed | |
NCT04587830 | ADI-PEG 20 (pegylated arginine deiminase) plus Radiotherapy and Temozolomide | Arginine metabolism, DNA replication | Glioblastoma multiforme | Phase II | Recruiting | |
NCT01910012 | ADI-PEG 20 (pegylated arginine deiminase) | Arginine metabolism | Acute myeloid leukemia | Phase II | Completed | |
NCT01910025 | ADI-PEG 20 (pegylated arginine deiminase) | Arginine metabolism | Non-Hodgkin’s lymphoma | Phase II | Completed | |
NCT00450372 | ADI-PEG 20 (pegylated arginine deiminase) | Arginine metabolism | Metastatic melanoma | Phase II | Completed | |
NCT02006030 | ADI-PEG 20 (pegylated arginine deiminase) plus transarterial chemoembolization | Arginine metabolism | Hepatocellular carcinoma | Phase II | Completed | |
NCT06034977 | ADI-PEG 20 (pegylated arginine deiminase) plus Lenvatinib | Arginine metabolism, kinase inhibition | Hepatocellular carcinoma | Phase II | Recruiting | |
NCT02709512 | ADI-PEG 20 (pegylated arginine deiminase) plus Pemetrexed and Cisplatin | Arginine metabolism, folate metabolism, DNA replication | Malignant pleural mesothelioma | Phase II/III | Completed | |
NCT05712694 | ADI-PEG 20 (pegylated arginine deiminase) plus Gemcitabine and Docetaxel | Arginine metabolism, DNA | Leiomyosarcoma | Phase III | Recruiting | |
NCT01287585 | ADI-PEG 20 (pegylated arginine deiminase) | Arginine metabolism | Hepatocellular carcinoma | Phase III | Completed | |
NCT05317819 | ADI-PEG 20 (pegylated arginine deiminase) | Arginine metabolism | Hepatocellular carcinoma | Phase III | Recruiting | |
TRYPTOPHAN | NCT03364049 | MK-7162 plus Pembrolizumab | Indoleamine 2, 3-dioxygenase (IDO) inhibitor, anti-PD-1 | Multiple solid tumors | Phase I | Completed |
NCT03792750 | BMS-986205 alone or in combination with Nivolumab | Indoleamine 2, 3-dioxygenase (IDO) inhibitor, anti-PD-1 | Multiple solid tumors | Phase I/II | Completed | |
NCT03516708 | Epacadostat plus radiation, CAPOX, FOLFOX | Indoleamine 2, 3-dioxygenase (IDO) inhibitor | Rectal cancer | Phase I/II | Recruiting | |
NCT00567931 | Indoximod (1-methyl-D-tryptophan) | Indoleamine 2, 3-dioxygenase (IDO) inhibitor | Multiple solid tumors | Phase I | Completed | |
NCT01191216 | Indoximod (1-methyl-D-tryptophan) and Docetaxel | Indoleamine 2, 3-dioxygenase (IDO) inhibitor | Multiple solid tumors | Phase I | Completed | |
NCT02502708 | Indoximod (1-methyl-D-tryptophan) plus Temozolomide | Indoleamine 2, 3-dioxygenase (IDO) inhibitor, DNA repair | Malignant brain tumor | Phase I | Completed | |
NCT02835729 | Indoximod (1-methyl-D-tryptophan) plus cytarabine and idarubicin | Indoleamine 2, 3-dioxygenase (IDO) inhibitor, DNA replication | Acute myeloid leukemia | Phase I | Completed | |
NCT01042535 | Indoximod (1-methyl-D-tryptophan) and Ad.p53 DC vaccine | Indoleamine 2, 3-dioxygenase (IDO) inhibitor, immunotherapy | Metastatic breast cancer | Phase I/II | Completed | |
NCT02052648 | Indoximod (1-methyl-D-tryptophan) plus Temozolomide | Indoleamine 2, 3-dioxygenase (IDO) inhibitor, DNA repair | Malignant brain tumor | Phase I/II | Completed | |
NCT02077881 | Indoximod (1-methyl-D-tryptophan) plus Gemcitabine and Nab-Paclitaxel | Indoleamine 2, 3-dioxygenase (IDO) inhibitor, DNA replication | Metastatic pancreatic cancer | Phase I/II | Completed | |
NCT02073123 | Indoximod (1-methyl-D-tryptophan) plus immune checkpoint inhibitors | Indoleamine 2, 3-dioxygenase (IDO) inhibitor, immune checkpoint | Metastatic melanoma | Phase I/II | Completed | |
NCT01560923 | Indoximod (1-methyl-D-tryptophan) and Provenge | Indoleamine 2, 3-dioxygenase (IDO) inhibitor, immunotherapy | Castration-resistant prostate cancer | Phase II | Completed | |
NCT01792050 | Indoximod (1-methyl-D-tryptophan) plus docetaxel or paclitaxel | Indoleamine 2, 3-dioxygenase (IDO) inhibitor, DNA replication | Metastatic breast cancer | Phase II | Completed | |
ADENOSINE | NCT04381832 | Etrumadenant | A2a, A2b receptor antagonist | Metastatic castrate-resistant prostate cancer | Phase I/II | Completed |
NCT05024097 | Etrumadenant plus Zimberelimab and radiation | A2a, A2b receptor antagonist; anti-PD-1 antibody | Rectal cancer | Phase II | Recruiting | |
NCT05915442 | Quemliclustat plus Etrumadenant and Zimberelimab | CD73 antagonist; A2a, A2b receptor antagonist; anti-PD-1 antibody | Prostate cancer | Phase II | Recruiting | |
NCT05886634 | Etrumadenant and Zimberelimab | A2a, A2b receptor antagonist; anti-PD-1 antibody | Liposarcoma | Phase II | Recruiting | |
NCT04660812 | Etrumadenant plus several drug combinations | A2a, A2b receptor antagonist | Metastatic colorectal cancer | Phase I/II | Active, not recruiting | |
NCT06048484 | Quemliclustat with Etrumadenant and Zimberelimab and radiation | CD73 inhibitor; A2a, A2b receptor antagonist; anti-PD-1 antibody | Pancreatic ductal adenocarcinoma | Phase II | Recruiting | |
NCT05688215 | Quemliclustat and Zimberelimab | CD73 inhibitor; anti-PD-1 antibody | Pancreatic adenocarcinoma | Phase I/II | Recruiting | |
NCT04306900 | TTX-030 | Anti-CD39 antibody | Multiple solid tumors | Phase I | Completed | |
NCT03884556 | TTX-030 | Anti-CD39 antibody | Multiple solid tumors | Phase I | Completed | |
NCT06119217 | TTX-030 with nab-paclitaxel, gemcitabine, and budigalimab | Anti-CD39 antibody; mitotic arrest; DNA synthesis; anti-PD-1 | Pancreatic adenocarcinoma | Phase II | Active, not recruiting | |
NCT05272709 | TT-702 | A2b receptor antagonist | Multiple solid tumors | Phase I/II | Recruiting | |
NCT04969315 | TT-10 | A2a, A2b receptor antagonist | Multiple solid tumors | Phase I/II | Active, not recruiting | |
NCT02655822 | Ciforadenant alone or with Atezolizumab | A2a receptor antagonist; anti-PD-L1 antibody | Multiple solid tumors | Phase I | Completed | |
NCT05501054 | Ciforadenant with Ipilimumab and Nivolumab | A2a receptor antagonist; anti-CTLA-4 antibody; anti-PD-1 antibody | Renal cell carcinoma | Phase I/II | Recruiting | |
NCT05117177 | Inupadenant | A2a receptor antagonist | Multiple solid tumors | Phase I | Completed | |
NCT05403385 | Inupadenant plus chemotherapy | A2a receptor antagonist | Non-small cell lung cancer | Phase II | Recruiting | |
NCT02403193 | Taminadenant alone or with PDR001 | A2a receptor antagonist; anti-PD-1 antibody | Non-small cell lung cancer | Phase I | Completed | |
NCT04089553 | AZD4635 plus Durvalumab or Oleclumab | A2a receptor antagonist; anti-PD-L1 antibody; anti-CD73 antibody | Prostate cancer | Phase II | Completed | |
NCT03274479 | PBF-1129 | A2b receptor antagonist | Non-small cell lung cancer | Phase I | Active, not recruiting | |
NCT05234307 | PBF-1129 and Nivolumab | A2b receptor antagonist; anti-PD-1 antibody | Non-small cell lung cancer | Phase I | Recruiting | |
NCT04336098 | SRF617 | Anti-CD39 antibody | Multiple solid tumors | Phase I | Completed | |
NCT03454451 | Mupadolimab alone or with Ciforadenant and/or Pembrolizumab | Anti-CD73 antibody; A2a receptor antagonist; anti-PD-1 antibody | Multiple solid tumors | Phase I | Completed | |
NCT03616886 | Oleclumab with Paclitaxel, Carboplatin, and Durvalumab | Anti-CD73 antibody; mitotic arrest; DNA damage; anti-PD-L1 | Triple-negative breast cancer | Phase I/II | Phase I/II | |
NCT03773666 | Oleclumab with Durvalumab | Anti-CD73 antibody; anti-PD-L1 antibody | Bladder cancer | Phase I | Completed | |
NCT05270213 | RBS2418 | Ectonucleotide pyrophosphatase/phosphodiesterase I (ENPP1) inhibitor | Multiple solid tumors | Phase I | Recruiting | |
POLYAMINES | NCT05717153 | Difluoromethylornithine (DFMO) and AMXT 1501 | Ornithine decarboxylase inhibitor; polyamine transport inhibitor | Glioma | Phase I | Recruiting |
NCT03536728 | Difluoromethylornithine (DFMO) and AMXT 1501 | Ornithine decarboxylase inhibitor; polyamine transport inhibitor | Multiple solid tumors | Phase I | Completed | |
NCT02030964 | Difluoromethylornithine (DFMO) with Celecoxib, Cyclophosphamide, and Topotecan | Ornithine decarboxylase inhibitor; chemotherapeutics | Neuroblastoma | Phase I | Active, not recruiting | |
NCT05500508 | Difluoromethylornithine (DFMO) and AMXT 1501 | Ornithine decarboxylase inhibitor; polyamine transport inhibitor | Multiple solid tumors | Phase I/II | Active, not recruiting | |
NCT06059118 | Difluoromethylornithine (DFMO) with Testosterone and Enzalutamide | Ornithine decarboxylase inhibitor; hormone; anti-androgen | Prostate cancer | Phase II | Recruiting | |
NCT00293488 | SL-11047 | Polyamine analog | Lymphoma | Phase I | Completed | |
NCT00086736 | Eflornithine and Bicalutamide | Ornithine decarboxylase inhibitor; anti-androgen | Prostate cancer | Phase II | Completed | |
NCT03794349 | Eflornithine and Irinotecan Temozolomide, and Dinutuximab | Ornithine decarboxylase inhibitor; chemotherapeutics | Neuroblastoma | Phase II | Active, not recruiting | |
NCT05254171 | SBP-101 with Nab-Paclitaxel and Gemcitabine | Polyamine analog; chemotherapeutics | Pancreatic cancer | Phase II/III | Recruiting | |
METHIONINE | NCT06568614 | SYH2039 | Methionine adenosyltransferase 2 alpha (MAT2A) inhibitor | Multiple solid tumors | Phase I | Not yet recruiting |
NCT04794699 | IDE397 | Methionine adenosyltransferase 2 alpha (MAT2A) inhibitor | Multiple solid tumors | Phase I | Recruiting | |
NCT06414460 | ISM3412 | Methionine adenosyltransferase 2 alpha (MAT2A) inhibitor | Multiple solid tumors | Phase I | Not yet recruiting | |
NCT05038150 | SGN1 (engineered Salmonella bacteria overexpressing L-methioninase) | Methionine metabolism | Multiple solid tumors | Phase I/II | Recruiting | |
NCT05103345 | SGN1 (engineered Salmonella bacteria overexpressing L-methioninase) | Methionine metabolism | Multiple solid tumors | Phase I/II | Recruiting | |
NCT05701553 | S-adenosyl-methionine (SAM) and anti-PD-1/PD-L1 antibodies | Methionine metabolism | Hepatocellular carcinoma | Observational | Recruiting |
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Share and Cite
Clay, R.; Li, K.; Jin, L. Metabolic Signaling in the Tumor Microenvironment. Cancers 2025, 17, 155. https://doi.org/10.3390/cancers17010155
Clay R, Li K, Jin L. Metabolic Signaling in the Tumor Microenvironment. Cancers. 2025; 17(1):155. https://doi.org/10.3390/cancers17010155
Chicago/Turabian StyleClay, Ryan, Kunyang Li, and Lingtao Jin. 2025. "Metabolic Signaling in the Tumor Microenvironment" Cancers 17, no. 1: 155. https://doi.org/10.3390/cancers17010155
APA StyleClay, R., Li, K., & Jin, L. (2025). Metabolic Signaling in the Tumor Microenvironment. Cancers, 17(1), 155. https://doi.org/10.3390/cancers17010155