Cancer at Nature Portfolio

Secondary and exploratory analyses of the phase 3 NRG GY018 trial show that, in patients with advanced or recurrent endometrial cancer, first-line treatment with pembrolizumab together with paclitaxel and carboplatin leads to prolonged progression-free survival, according to blinded independent central review.

Minimal tumour perturbations that boost T-cell infiltration can be discovered by using deep learning to analyse large-scale spatial omics profiles of tumours.

The role of cancer associated fibroblasts (CAF) in immunotherapy response of gastric cancer (GC) is elusive. Here, by single cell sequencing, spatial transcriptomic and functional evaluation, the authors identify antigen-presenting CAF (apCAF) with high MHC II, which is correlated with immunotherapy responsiveness of GC patients.

Targeting cancer stem cells (CSCs) has great potential in anti-cancer treatment. Here this group reports the role of antibiotic Nifuroxazide as a potent anti-CSC compound and fabricates it into an anti-breast CSC prodrug using click chemistry strategy.

Deregulation of the Phosphoinositide 3-kinase (PI3K) pathway is associated with metabolic flexibility leading to cancer poor prognosis. Here, the authors show that targeting both glutamine degradation and mTOR inhibition effectively kills PI3K-altered cancer cells in pre-clinical and clinical settings for T-cell acute lymphoblastic leukemia and solid cancer.

The connection between amino acid metabolism and pyroptosis remains elusive. Here, the authors show that the methionine metabolite spermidine inhibits GSDME-mediated pyroptosis by dampening GSDME-NT endocytosis, which can be targeted to promote anti-tumor immunity.

‘Small cell lung cancers do not respond well to immune checkpoint blockade therapy, due to the poor recruitment of CD8 + T cells to the tumours. Here authors show that via combining radiotherapy, PARP inhibitors and anti-PD-L1 treatments, T cell infiltration and function could be improved via mechanisms that increase the chemo-attractants CCL5 and CXCL10.

The CDK4/6 inhibitor ribociclib holds promise in cancer therapy but how cell cycle inhibitory drugs affect the anti-tumor immune response remains a question. Here authors show that poor response of early-stage estrogen receptor positive breast cancers to ribociclib is caused by changes in the immune cell composition and cancer-cell-immune-cell communication in the tumors rather than intrinsic cancer cell resistance to cell cycle inhibition.

Fan et al. report a role for PRMT5 in regulating GPX4 stability and ferroptosis sensitivity through arginine methylation, which may be targeted to inhibit tumour development.

Duan, Hu, Han, Lei, Wang et al. report that ADSL-mediated production of fumarate suppresses STING activation and impairs T cell and NK cell infiltration, thereby facilitating immune evasion in breast cancer.

Reduced dietary fibre together with mutations in the host mismatch repair machinery promote colon carcinogenesis by increasing inflammation, nitrate-fuelled growth of colibactin-producing Escherichia coli and colibactin-dependent genotoxic tissue damage.

The authors develop multimodal machine learning models to infer metastatic recurrence risk for early-stage, hormone receptor-positive breast cancer from H&E images using >6000 cases across three centers, outperforming a nomogram and unimodal methods.

Existing methods for identifying differential gene expression signatures for clinical case/control analyses with high throughput sequencing data present various challenges. Here, the authors develop BEANIE, a nonparametric statistical method that outperforms existing approaches for simulated and real-world cancer datasets, revealing biologically and clinically relevant insights.

A framework for building foundation models using diverse patient data can enhance survival prediction and provide interpretable insights into treatment response. Here, the authors show that their approach outperforms existing methods while integrating generative and interpretable modules to reveal clinically relevant biological insights.

Retinoic acid is known to be effective against bone marrow metastatic neuroblastoma cells, but not primary tumors. Here, authors discover that bone morphogenetic protein signaling is responsible for determining neuroblastoma cell fate and sensitivity to retinoic acid.

Here authors show that EVs derived from hepatocellular carcinomas may contain the long noncoding RNA, HDAC2-AS2, which suppresses antitumour CD8 + T cells by interfering with transcriptional and epigenetic regulation of their activated, cytotoxic functional state.

LINE-1 activity was quantified in a large, pan-cancer dataset, finding locus-specific heterogeneity and new associations using a computational pipeline. A mathematical mediation model of p53 and L1 interactions was inferred. Somatic retrotransposition was seen in Li-Fraumeni Syndrome with heritable TP53 mutations.

Genetic and environmental factors influence lifespan. Here, the authors analyse UK Biobank data to identify common and rare lifespan-associated variants, many of which are linked to cancer and clonal haematopoiesis.

MethyLYZR, an epigenetic classifier of brain tumors, provides clinically relevant cancer classification results within 15 min of sequencing, with potential applications for neurosurgical intraoperative use.

A patient with newly diagnosed glioblastoma was safely treated with neoadjuvant nivolumab, relatlimab and ipilimumab before maximal resection, with comprehensive immune profiling showing the induction of overall immune activation early during treatment. The patient had no definitive evidence of recurrence at 17 months after treatment.

Bilen et al. perform a phase 2 single-arm clinical trial of neoadjuvant cabozantinib in patients with locally advanced nonmetastatic clear cell renal cell carcinoma, assess efficacy and find antitumor CD8⁺ T cell response activation upon treatment.

The p85 regulatory subunit of phosphoinositide 3-kinase (PI3K) exists in two major isoforms: p85-alpha and -beta. Here, the authors reveal that p85-beta has a unique nuclear activity where it regulates gene transcription and contributes to tumorigenesis.

Early-onset lung cancer in young adults remains poorly studied. Here, the authors analyse the clinicopathological, molecular, and immune features of early-onset non-small cell lung cancers in a cohort of 421 patients across ten medical centres in China, identifying potential therapeutic strategies for this subgroup.

A study of myeloid cells in gliomas, a type of brain tumour, used a factor-based computational framework to reveal four immunomodulatory gene-expression programs that are expressed across myeloid cell types, driven by microenvironmental cues and predictive of therapeutic response.

Radiation-therapy-induced DNA damage in oral and rectal epithelial cells can be reduced via the nanoparticle-mediated local delivery of messenger RNA encoding for a damage-suppressor protein found in radiation-resistant tardigrades.

UniPMT, a multitask learning model, is presented, which integrates three key biological relationships into a unified framework for accurate peptide–MHC–TCR binding prediction.

Immune receptors regulate immune responses and are key cancer immunotherapy targets. Here, the authors designed helical concave scaffolds to bind convex sites in immune receptors, creating high-affinity protein binders for TGFβRII, CTLA-4, and PD-L1. Co-crystal structures confirmed their therapeutic potential.

8q24 is the most frequently amplified region in human cancers. Here, authors discover that ZNF252P, located in 8q24, promotes tumorigenesis by regulating a c-Myc-mediated positive feedback loop through phase separation of HNRNPK and ILF3.

In this Review, Bruhm et al. provide a comprehensive overview of targeted and genome-wide cell-free DNA detection approaches, examining their potential to complement existing screening programmes or enhance early cancer detection for those cancers without effective screening methods.

Immunoengineering-based cancer therapies have huge potential. Here the authors report on the lipid nanoparticle delivery, to cancer cells, of self-amplifying RNA encoding SARS-CoV-2 spike epitope-loaded MHC I molecules to take advantage of anti-SARS-CoV-2 immunity from a vaccinated population to treat cancer.

This Review explores the intersection between cancer and aging, illustrating shared causal mechanisms including genome instability, telomere dysfunction, cellular senescence and dysregulated immunity and how these can be explored in animal models.

Single-cell RNA sequencing has transformed our understanding of the biology of cancer cells and that of nonmalignant cells present in the tumour microenvironment. However, how this new knowledge can be translated into improved outcomes for patients often remains uncertain. In this Review, the authors describe the results of single-cell RNA analyses of samples from patients with cancer with an emphasis on how the findings of these studies have, or are anticipated to lead to, improved patient outcomes, with a focus on four key aspects: refinement of tumour subtyping, characterization of treatment-induced changes, identification of gene expression programmes predictive of treatment response and resistance, and the discovery of novel therapeutic targets.

In this broad Review, the authors describe how the immune response to leukemias develops, how these cancer cells avoid it and how various immunotherapies have been designed to overcome resistance.

This Review discusses the mechanisms and origins of cardiovascular risks associated with prostate cancer therapies, mainly focusing on differences between gonadotropin-releasing hormone agonists and antagonists. Cardiovascular risks associated with all other available prostate cancer treatments are also discussed.

CD19-targeted CAR T cells have transformed the management of patients with relapsed and/or refractory large B cell lymphoma, and these therapies are increasingly being administered as earlier-line therapies. Nonetheless, the prognosis of these patients is often difficult to predict, with various prospective and real-world studies suggesting that a wide range of factors are associated with treatment outcomes. In this Review, the authors summarize these various associations as well as their implications for patient selection and management.

In this Review, the authors describe the intricate interplay of chemo-radio-immuno-sensitization in advanced penile squamous cell carcinoma with human papillomavirus (HPV) co-infections. By drawing parallels with other HPV-driven tumours, they provide arguments for the development of effective therapeutic strategies tailored to the unique characteristics of advanced penile squamous cell carcinoma with HPV co-infection.

McGaha and colleagues review recent research on the metabolic programs of tumor-associated macrophages across cancer types and discuss their implications on potential therapeutic vulnerabilities.

This Review discusses how microfluidic and other fluidic devices can be leveraged at each stage of cell manufacturing for enhancing the potency, predictability and affordability of adoptive cell therapies.

The authors of this Perspective evaluate the developments in the use of artificial intelligence (AI) in digital pathology for oncology applications between 2019 and 2024, addressing technological innovations, regulatory trends, implementation and financial implications. Importantly, they explore the current landscape of clinical deployment, highlighting future opportunities for the integration of AI into clinical oncology routine practice.

Dendritic cells (DCs) shape the adaptive immune response to peripheral tissue antigens and, as such, are crucial for mounting an effective antitumour immune response in cancer. This Review outlines the molecular basis of DC maturation, highlights the mechanisms through which cancer impairs DC maturation and considers the potential for DC-focused cancer immunotherapeutics.

In this Review, Suvac et al. discuss how intratumoural hypoxia is a driving force in tumour evolution, alongside driver gene mutations, through the generation of genomic instability. The resultant selected unstable tumour clones underpin resistance to local and systemic therapies and unfavourable outcomes for patients with cancer.

Analysis of circulating tumour DNA (ctDNA) is commonly used for molecular profiling in patients with advanced-stage non-small-cell lung cancer (NSCLC). The authors of this Review summarize the available evidence on the potential utility of incorporating ctDNA in the management of those with early stage and locally advanced NSCLC and propose interventional studies to provide the necessary additional evidence.

In this Review, Erez and colleagues examine the complex interactions among tumours, their microenvironment and the host, shaping a metabolic macroenvironment that drives cancer progression. They explore how this crosstalk impacts on metastasis, inflammation and cachexia, providing insights for enhanced cancer management.

In this Review, the authors present an overview of epigenetic alterations implicated in prostate cancer pathophysiology, focusing on epigenetic diagnostic and prognostic biomarkers. Development and potential for future clinical implementation of epidrugs targeting epigenetic modifications for prostate cancer treatment are also discussed.

Tumour-infiltrating lymphocytes (TILs) are crucial effectors of the anticancer immune response and are hypothesized to be key determinants the efficacy of immune-checkpoint inhibitors (ICIs). Herein, the authors review studies that have evaluated the roles of various TIL subsets as predictive biomarkers for ICIs, as well as opportunities, challenges and strategies for future research in this field.

This Review discusses the current challenges and the available methods to study the four physical hallmarks of cancer.

Genomic mutations can be translated into modified functional proteins, impacting protein–protein interactions (PPIs) and thus altering cellular functions. In this Review, Fu, Mo and Ivanov summarize the mechanisms by which oncogenic mutations impact PPIs, technologies for monitoring this, the categories and features of PPIs in cancer, and finally the therapeutic implications of this.

Despite lower levels of most targetable alterations, a strong association with a history of smoking and generally higher levels of PD-L1 expression, patients with squamous non-small-cell lung cancer (LUSC) have inferior outcomes on immune-checkpoint inhibitors (ICIs) compared to those with non-squamous disease. In this Review, the authors describe the available evidence on the role of ICIs and of potential novel therapies in patients with LUSC, as well as highlighting important unresolved challenges and future research directions in this historically overlooked subtype.

In this Review, the authors discuss key clinical trials and therapeutic advances that have informed the current treatment landscape for cervical cancers of all stages, including refinement of surgical management approaches, the establishment of chemoradiotherapy, and the integration of anti-angiogenic agents, immune-checkpoint inhibitors and antibody–drug conjugates.

Gabrilovich and colleagues discuss how the functional diversity of neutrophils in cancer can be ascribed to two functional states: classically activated neutrophils and pathologically activated myeloid-derived suppressor cells.

Loss of Y chromosome (LOY), the most commonly occurring post-zygotic (somatic) mutation in male individuals, affects immune activity and is associated with cancer, neurodegeneration, cardiovascular disease and infection. LOY is dynamic over time and has cell-type-specific effects, suggesting its potential as a biomarker and therapeutic target.

Neoadjuvant administration of immune-checkpoint inhibitors (ICIs) has substantially improved the outcomes in patients with various solid tumours, including those with head and neck cancer. However, not all patients derive benefit, indicating a need for biomarkers that enable accurate predictions of a response to these agents. In this Review the authors describe changes in both intratumour and circulating T cells in patients with locally advanced head and neck cancer receiving neoadjuvant ICIs, and consider the role of specific T cell subsets as biomarkers in this setting.

Leptomeningeal metastatic disease (LMD) arises secondary to the metastatic dissemination of cancer cells into the leptomeninges and cerebrospinal fluid. Novel therapies against systemic disease have not yet translated into improved outcomes for patients with LMD, in whom median survival after diagnosis remains at 2–6 months. The authors of this Review, a multidisciplinary group of experts, describe the emerging evidence and areas of active investigation in LMD and provide directed recommendations for future research.

Hepatocellular carcinoma (HCC) accounts for approximately 80% of all cases of primary liver cancer, the third leading cause of cancer mortality worldwide. In this Review, the authors discuss current and emerging preventive strategies to reduce HCC risk, especially in individuals with chronic liver diseases.

Over the past few years, several novel therapies, including targeted therapies for specific subgroups as well as several non-targeted therapies, have been developed and approved for patients with chemorefractory metastatic colorectal cancer (CRC). Nonetheless, selecting patients who are most likely to benefit from one specific therapy is challenging owing to a lack of direct comparisons of the efficacy of these agents in specific settings. In this Review, the authors summarize the available evidence on the efficacy and safety of later-line therapies for patients with advanced-stage CRC and suggest an evidence-based treatment-selection algorithm.

In 2024, important studies highlighted the ongoing global battle against liver cancer, a deadly yet common cancer. Despite advances in treatments, obstacles persist in early detection and equity in healthcare access. The journey towards improving patient outcomes remains bumpy. Gaining insights from failures is critical for effectively tackling this persistent health threat.

Chromothripsis is an extreme form of chromosome instability that causes the acquisition of multiple genomic aberrations. Simovic-Lorenz and Ernst discuss mechanistic models of chromothripsis and outline its role in cancer development and tumour evolution. Vulnerabilities of chromothriptic tumours that could be therapeutically exploited are also discussed.

Several chimeric antigen receptor (CAR) T cell therapies are approved for the treatment of various haematological cancers; however, they are all autologous products requiring individualized manufacturing for each patient, which presents technical, logistical and resource challenges that limits scalability and implementation, and even raises certain ethical questions. Allogeneic products have the potential to address many of these issues, but come with their own challenges. This Review summarizes the advantages and disadvantages of allogeneic CAR cell products derived from T cells or other immune cells, their engineering and progress towards clinical implementation, as well as hurdles that remain to be overcome.

l-Asparaginase (L-ASP) is a standard therapy for leukemias but not solid tumours. In a compassionate-use trial for nasopharyngeal carcinoma, Chang et al. report that L-ASP enhances the anti-tumour T cell response with clinical benefits when combined with pembrolizumab. This study provides proof of concept for ‘metabolic-immunotherapy’ in cancer.

Wildfires emit carcinogenic pollutants, raising long-term cancer risks in affected populations. In this Comment, Weichenthal highlights these concerns and outlines actionable solutions to reduce exposure and mitigate risks.

A new study reveals that the RAF isoform ARAF uniquely forms solid-like granules at the cell membrane that have a key role in regulating RAS activation levels and contribute to drug resistance.

Recent studies in mouse models of viral infection showed that precursors of terminally exhausted T cells emerge early during the course of disease. Here, Galluzzi discusses these findings and what they may mean for our understanding of tumour immunology and responses to immunotherapy with immune checkpoint blockade.

Synonymous mutations can promote tumorigenesis by perturbing m⁶A modification of tumour suppressor mRNAs.

Patients with advanced-stage cancer seek treatments that prolong survival and improve quality of life. We analysed new anticancer drug indications approved by the FDA and EMA between 2020 and 2023 using the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale quality-of-life checklist. Our findings highlight critical gaps in the availability and reliability of quality-of-life outcomes from the pivotal trials that support these approvals.

While cancer treatments are essential for patient survival, they often induce premature ageing-related conditions in survivors. In this Comment, Demaria outlines how understanding the underlying molecular mechanisms of this is crucial for developing integrated strategies to improve long-term health outcomes in survivors.

Autophagy, thought to be boosted by T cell receptor or cytokine stimulation, took an unexpected turn in the findings of Sinclair et al. — it is suppressed in activated T cells, facilitating their effector functions.

Anti-PIT1 hypophysitis is a form of paraneoplastic autoimmune hypophysitis. The condition is attributable to the ectopic expression of pituitary-specific positive transcription factor 1 (PIT1) in tumour tissues, which leads to autoimmunity against PIT1-positive anterior pituitary cells. In the past few years, it has been reported that anti-PIT1 hypophysitis can occur as an immune checkpoint inhibitor-related hypophysitis.

In a recently reported study, a novel engineered oncolytic Newcastle disease virus encoding porcine α1,3-galactosyltransferase was evaluated in monkeys with CRISPR-induced primary hepatocellular carcinoma and in a phase I clinical trial. The virus induced hyperacute tumour rejection and an objective response rate of 35% in 20 evaluable patients. This approach highlights the promises and challenges of oncolytic virus drug development.

The tumor microenvironment has a crucial role in tumor progression and metastasis formation. A single-cell analysis now compares the microenvironments of primary tumor and peritoneal metastases in colorectal cancer and shows that neutrophils and fibroblasts contribute to the unique biology of peritoneal metastatic disease.

Prostate cancer is the most common cancer in men, yet disparities persist in screening, diagnosis and treatment among populations with low socioeconomic status. Minority groups face barriers to clinical trial inclusion including limited awareness and financial challenges. Promoting diversity in clinical trials is crucial for inclusivity, improving treatment efficacy and achieving equitable health outcomes in prostate cancer care.

Pancreatic tumours hijack neuronal signalling mechanisms to boost cancer growth. A technology to identify and profile mouse neurons that connect the spinal cord to pancreatic cancer might improve treatment of this disease.

Many conventional small-molecule drugs work by inhibiting proteins, affecting their function. One small molecule instead imbues a protein with a new function in a mechanism that could inform rational drug design.

Cancer phylogenetic trees describe the evolutionary relationship between primary tumors and metastatic sites. A study now shows that mutations in guanine homopolymer microsatellites represent accurate molecular clocks, revealing the number of cell divisions that have occurred during cancer development and progression.

CAR-T-cell therapy treated a girl with a rare childhood cancer, raising hopes for future recipients of the approach.

The deadly cancer is often not found until it has spread to other parts of the body.

DeepGEM, an artificial intelligence (AI)-based model, accurately predicts the presence of key genomic alterations in histological slides prepared from samples obtained from patients with lung cancer. This approach provides a cost-effective alternative to genomic testing, generates spatial mutation maps and might support personalized treatment strategies. Validated in diverse datasets, DeepGEM highlights the potential of AI to transform precision oncology and improve global healthcare equity.

A small but in-depth study of allogeneic CAR T cell therapy in patients with high-risk neuroblastoma shows feasibility and potential efficacy, and mechanistic insights reveal pathways to improved functionality of CAR T cells in solid tumors.

Layered control of oncogenic protein dosage enables the hallmarks of cancer, but specific regulators of oncogene mRNA translation remain unknown. A study now reports RMB42 as a regulator of the MYC by remodelling its RNA structure and increasing translation efficiency, highlighting a potential therapeutic avenue to target MYC-driven cancers.

A new study reveals that in drastic contrast to other cancer types, translocation renal cell carcinoma (tRCC) is transcriptionally rewired towards an oxidative phosphorylation (OXPHOS) state, which renders tRCC vulnerable to interventions that promote NADH reductive stress, highlighting how the maintenance of the optimal redox state in cancer can be therapeutically exploited.

Mass spectrometry-based proteomic studies involve tissue lysis. Herein, we updated our 2018 protocol¹ by implementing a sonication step into urea-based tissue lysis to improve the detection of membrane-bound and DNA-binding proteins.

Behavior-guided transcriptomics is an extension to the BEHAV3D protocol, for the integration of T cell live-imaging data with single-cell transcriptomics, enabling analysis of gene programs linked to dynamic T cell behaviors.

Establishment and robust expansion of human fetal brain organoids, their characterization and adaptation for downstream analyses, and how to genome engineer them to generate bottom-up brain tumor models.

We present a practical workflow for end-to-end weakly supervised deep learning to predict biomarkers directly from whole-slide images, enabling clinical researchers to work with engineers to set up a complete computational pathology project.

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.