Cancer at Nature Portfolio

In glioblastoma, malignant cells can escape surgical resection by migrating into the surrounding healthy brain tissue. Here, the authors use spatial transcriptomics to characterise the tumour core and infiltrated brain regions in glioblastoma, and show shifts in malignant cell composition and molecular pathways with potential clinical implications.

The pathogenesis of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) remains to be understood. Here the authors identify that USP26 deubiquitinase drives the progression of HBV-associated HCC via regulating the protein stability of Sirtuin 1.

Post-translational modifications regulate tumorigenesis and cancer therapy sensitivity. Here, the authors show that N-glycosylation defective Interleukin-6 (deNG-IL6) switches downstream signalling pathway from JAK-STAT3 to SRC-YAP axis and lung cancer cells secrete deNG-IL6 to promote metastasis and tyrosine kinase inhibitor resistance.

CRISPR screen identifies coactivators of the androgen receptor (AR) complex, including NSD2. NSD2 contributes to AR cistrome reprogramming during prostate cancer progression, and its degradation via a novel PROTAC reduces prostate cancer cell viability in vitro.

A commercial near-infrared dye that is sensitive to apoptosis and that provides high tumour-to-muscle and tumour-to-liver contrast ratios facilitates fluorescence-guided tumour screening, tumour resection and the assessment of wound healing.

The molecular mechanisms underlying merlin-intact meningioma growth remain to be explored. Here, the authors show that merlin activates Wnt signalling and tumour growth through its dephosphorylation on serine 13 attenuating the inhibitory interactions with β-catenin.

Despite being a hallmark of cancer, the identification of targetable vulnerabilities of aneuploid cancer cells remains limited. Here, the authors develop RPE1-hTERT cell lines with varying degrees of aneuploidy to investigate the consequences of chromosomal imbalance, identifying CRAF as an aneuploid-selective therapeutically targetable vulnerability.

Guo, Hong et al. report that TET2 condensation maintains proper DNA demethylation at specific genomic loci, which can be targeted to alter gene expression and impair leukaemia growth.

Here, the authors show that bromodomain-containing protein 4 is recruited to the MYC enhancer by Mediator and activates transcription through elongation factors independently of bromodomains. This mechanism contributes to bromodomain and extraterminal domain inhibitor resistance in estrogen receptor-positive breast cancer.

Meguro et al. show an accumulation of p16^high senescent fibroblasts in the aging bladder that serves as a cancer-permissive niche and promotes tumor growth by secreting CXCL12. Inhibition of senescence or CXCL12 signaling suppresses bladder tumor growth.

VirtualMultiplexer is a generative AI tool that produces realistic multiplexed immunohistochemistry images from tissue biopsies. The generated images could be used to improve clinical predictions, enhancing histopathology workflows and accelerating cancer research.

Head and neck squamous cell carcinoma can occur with and without the presence of HPV infection. Here, the authors utilise Mendelian randomization to assess the causal effects of smoking and alcohol on HPV-positive and HPV-negative head and neck cancer development.

Optical nanoprobes with preferential tumour accumulation is often limited by inefficient amplification of biological signals. Here, the authors report a hydrophobic core-tunable nanoprobe orthogonally amplifying tumour microenvironmental signals and demonstrating clear delineation between malignant lesions and normal tissues on multiple tumour models.

The hypoxia inducible factor HIF-1α has been shown to regulate T cell metabolism and function. Here authors deleted the prolyl hydroxylase domain-containing enzymes PHD2 and 3, thereby stabilizing HIF-1α, in therapeutic CD8 T cells to achieve better functionality upon adoptive transfer to tumour-bearing mice.

Dissecting the associations between exposure to environmental pollution and cancer risk remains crucial. Here, the authors evaluate the impact of air and water pollution on cancer incidence in China using a spatial evaluation system and show that most excess cancer cases occurred in areas with the highest level of co-pollution.

Dong et al. present an integrative proteogenomic analysis of high-risk prostate cancer samples from a cohort of Chinese patients and highlight potential therapeutic vulnerabilities and diagnostic markers.

Histone H3-mutant gliomas are deadly brain tumours and the tumour microenvironment is not fully understood. Here the authors profile the immune microenvironment from human samples and mouse models and implicate myeloid cells in immune suppression and show inhibition of myeloid cells and checkpoint blockade demonstrates therapeutic benefits in mice.

The interactions between tertiary lymphoid structures (TLS) and tumor cell aggregates remain to be investigated. Here, single-cell and spatial transcriptomics reveal the cellular composition, formation, and function of TLS during tumour progression and immunotherapy response in nasopharyngeal carcinoma.

Tamagawa, Fujii et al. demonstrate that squamous differentiation in human pancreatic cancer can be attributed to TP63-mediated lineage conversion and epigenetic reprogramming that depends upon a hypoxic and Wnt-defective niche.

The authors use lineage tracing to map the fate of wild-type and Brca1^{−/−};Trp53^{−/−} cells in the adult mouse mammary gland, identifying three layers of protection that limit the spread of mutant cells at the expense of allowing a minority of mutant cells to expand, which leads to field cancerization.

Formalin fixation is commonly used in tissue storage; however, this process has traditionally limited downstream whole genome sequencing usage. Here, the authors identify artefactual signatures in FFPE-derived sequencing data and demonstrate the preservation of clinical utility, thus enabling FFPE whole genome sequencing when required.

The life of RNAs is governed by a series of transcriptional and post-transcriptional steps. Here, authors developed Nanodynamo, an experimental and computational workflow for studying how the coordinated action of these steps shapes breast cancer gene expression programs at the subcellular level.

A study describes the development of a generalizable foundation machine learning framework to extract pathology imaging features for cancer diagnosis and prognosis prediction.

Immune checkpoint blockade (ICB) has shown promising activity in patients with advanced endometrial cancer, however its potential in the context of loco-regional disease remains unclear. Here the authors report the results of a phase I trial of neoadjuvant pembrolizumab (anti-PD1) in patients with mismatch repair deficient resectable endometrial cancer.

The response of prostate cancer cells to androgens depends on the dose. Here, the authors show that low levels of androgens function through androgen receptor (AR) monomers to activate mTOR and promote cell proliferation, while high dose androgens induce AR dimerization to inhibit c-MYC expression and facilitate cell differentiation.

Co-delivery of TLR7/8 agonists and TGF-β inhibitors (TGFβi) has the potential to overcome immunosuppression in the tumor microenvironment. Here the authors describe the application of the CarboCell technology for the sustained intratumoral release of a TLR7/8 agonist alone or in combination with a TGFβi, promoting anti-tumor immune responses in preclinical cancer models.

In this Review, Arpinati et al. summarize how the extracellular matrix, produced primarily by cancer-associated fibroblasts, impacts tumour progression, metastasis and therapy response through modulation of T cell-mediated antitumour immunity and propose routes to target these mechanisms therapeutically.

PIONEER is a European network of excellence for big data in prostate cancer, which brings together private and public stakeholders from nine countries in one multidisciplinary research consortium. In this Perspectives, members of the consortium detail the achievements of PIONEER and describe its goal of maximizing the potential of big data to improve prostate cancer care in the future.

In this Perspective, the authors provide an overview of the most promising deregulated non-coding RNAs in clear-cell renal cell carcinoma, discussing the role of different classes of non-coding RNAs in clear-cell renal cell carcinoma development and progression. Future perspectives and challenges associated with the translation of these markers into clinical practice are also discussed.

Targeting the interactions between neurons, cancer cells and other elements in the tumour microenvironment represents a potential paradigm shift in cancer treatment. This Review article provides an overview of the dynamics of the nerve–cancer cell interplay as well as a discussion of current preclinical and clinical evidence of the benefits of targeting the nervous system in cancer.

Although ovarian cancer is considered an immunoreactive disease, moderate to no efficacy has been shown in the trials testing immune-checkpoint inhibitors in these patients performed thus far. The authors of this Review summarize these results and propose a systematic classification of ovarian cancer based on CD8⁺ T cell immunophenotypes that, integrated with genetic data, can enable the design of tailored therapeutic approaches, including adoptive cell therapy and novel immunotherapy combinations.

In this Tools of the Trade article, Radhika Mathur describes the development of a novel 3D whole-tumour sampling approach for glioblastoma, which can be used to elucidate tumour heterogeneity.

Pan et al. performed a large-scale, cluster-randomized controlled trial to assess whether eradicating Helicobacter pylori in asymptomatic individuals would be beneficial in preventing gastric cancer.

The development of clinically relevant artificial intelligence (AI) models has traditionally required access to extensive labelled datasets, which inevitably centre AI advances around large centres and private corporations. Data availability has also dictated the development of AI applications: most studies focus on common cancer types, and leave rare diseases behind. However, this paradigm is changing with the advent of foundation models, which enable the training of more powerful and robust AI systems using much smaller datasets.

Cancer-promoting mutations are common in healthy tissue but rarely lead to tumour formation. A study of the mouse mammary gland reveals three protective mechanisms that limit the ability of cells to give rise to cancer.

Artificial intelligence (AI) is transforming prostate cancer management from diagnosis to treatment. AI tools have been designed for the analysis of digitized histopathology and MRI scans, generation of synthetic CT scans and improvement of robotic surgical outcomes. This progress underscores the need for regulation and the development of safe, ethical and non-biased software.

Point-of-care manufacturing and technology transfer can deliver cellular gene therapies at an affordable cost to patients across the world.

The human brain is usually considered to be beyond the reach of most immune cells. However, analysis of people who have brain tumours has revealed tumour-targeting T cells of the immune system in skull bones near the cancer site.

The tumour microenvironment propagates stress responses in resident cells. In tumour-infiltrating natural killer (NK) cells, the HSF1 transcription factor binds to mediators of effector function, negatively regulating NK cytotoxicity. These findings provide important mechanistic insights that may enhance NK cell cancer therapy.

Epigenetic therapy triggers myriad transposable elements to generate new antigens that could prime tumor cells for immunotherapy. A study of glioblastoma discovers indiscriminate activation in healthy cells as well, and presents a more selective strategy for potential therapeutic targeting.

My close experience with cancer and interactions with other patients, caregivers and health-care providers have shaped my belief that patients must be at the centre of research and care. In this Comment, I advocate for a redirection of research efforts in order to measure patient-centred outcomes and address health disparities.

The clinical utility of immune checkpoint inhibitors is limited by immune-related adverse events (irAEs); understanding the mechanisms of irAE development is thus crucial. A study reports that IL-17A-expressing CD4⁺ T cells were elevated at irAE onset and provides proof of concept for using IL-17A blockade to improve irAEs in two patients.

Using single-cell RNA sequencing analysis of bone-colonizing tumour cells and in vivo screening, lymphotoxin-β (LTβ) was identified as a key factor promoting bone colonization and outgrowth of breast cancer metastases. Blocking LTβ signalling significantly suppressed bone metastasis, highlighting its potential as a therapeutic target for breast cancer with bone metastatic disease.

Bacteria in the gut can affect the chemically induced growth of tumours in other parts of the body. Certain gut bacteria convert nitrosamine compounds, which are found in cigarette smoke and processed food, into metabolites that trigger the growth of tumours in the bladders of mice.

The authors introduce MACHETE (molecular alteration of chromosomes with engineered tandem elements), a clustered regularly interspaced short palindromic repeats directed Cas9-based system for the efficient deletion of megabase-sized genomic regions.

CONIPHER is a computational framework for accurately inferring subclonal structure and the phylogenetic tree from multisample tumor sequencing, accounting for both copy number alterations and mutation errors.

This protocol presents a computational approach to scoring drug sensitivity that integrates multiple dose–response parameters into a single response metric and identifies differences in drug-response patterns between cancer cells and healthy control cells.

Invasion–adhesion-directed expression sequencing adapts the 10x Genomics 5′ single-cell RNA sequencing protocol to enable generation of bacterial and eukaryotic DNA libraries to identify adherent or invasive bacteria and the associated host transcriptome at a single-cell level.

The authors present a protocol for genome-wide clustered regularly interspaced short palindromic repeat screening of three-dimensional neurospheres.

The current serum tumour markers α-fetoprotein, human chorionic gonadotrophin, and lactate dehydrogenase show limited value for testicular cancer relapse detection. A recent study highlights that false-positive elevations in follow-up monitoring are common and, conversely, many patients do not have elevations despite proven relapse. These findings highlight the potential for circulating microRNAs to be used as improved biomarkers for relapse detection.

A newly composed single-cell transcriptomic atlas of tumor-infiltrating T cells across 16 cancer types revealed previously undescribed T cell states and heterogeneity. A unique T cell stress response state, T_STR, was linked to immunotherapy resistance. Our high-resolution T cell reference maps, web portal, and annotation tool can assist efforts to develop T cell therapies.

Therapeutic products containing CD8⁺ and CD4⁺ T cells expressing CARs are effective at inducing remission in patients with cancer. How CD4⁺ CAR T cells contribute to the anti-tumor response has not been well established. A study uses syngeneic models and in vivo imaging to glean mechanistic insights into how CD4⁺ T cells target tumors.

Antigen presentation is fundamental to anti-tumor immunity, but our understanding of the physiological and molecular inputs to the process in different contexts remains limited. Two new studies explore the contribution of cell-intrinsic proteolytic mechanisms and cell-extrinsic hot and cold tumor microenvironments in shaping the antigenic landscape in lung cancer.

A preprint by Lad et al. shows that tumour-associated neutrophils in glioblastoma originate from skull bone marrow and acquire an antigen-presenting cell phenotype intratumorally in the presence of local T cells.

In this study, Insco et al. find patient-specific CDK13 mutations to impede RNA surveillance, leading to the accumulation and translation of prematurely terminated RNAs that drive malignancy in melanoma models.

An article in Nature Biomedical Engineering reports a simple and hardware-independent peptide-mediated delivery method for the CRISPR-mediated engineering of T cells.

An assay based on the electrophoresis of whole-cell lysates embedded in agarose plugs separates soluble from immobilized proteins, enabling the purification and the subsequent identification of DNA–protein cross-links.