Cancer at Nature Portfolio

Comprehensive molecular characterisations could shed light on the high heterogeneity and poor prognosis of gliomas. Here, the authors perform proteomic profiling of 188 glioma patients, revealing immune and metabolic neuron-related subgroups as well as metabolic biomarkers linked to prognosis.

Chimeric antigen receptor T (CAR-T) cell therapy is efficient in certain haematologic malignancies, but clinical success in solid tumours has been hampered by scarcity of tumour-specific antigens. Here authors show that combination therapy using CAR T cells targeting p95HER2 and bispecific antibodies against HER2 and CD3 consistently leads to complete regression in HER2-positive, patient-derived xenografts tumours in mouse models.

Yang et al. show that transcription–replication collisions lead to large tandem duplications, which are frequent in female-enriched, upper gastrointestinal tract and prostate cancers and are associated with poor survival and mutations in specific genes, such as CDK12.

Effective strategies to enhance T cell anti-tumor cytotoxicity are pivotal to improve treatment outcomes. By analyzing tumor samples from patients with head and neck or colon cancers, here the authors show that IL-12 can induce the expression of the inhibitory receptor NKG2A on tumor-reactive CD8 cytotoxic lymphocytes.

A framework combining combinatorial CRISPR knockout in breast, lung and oropharyngeal cancer in vitro models with public data identifies synthetic lethal interactions, such as perturbed KDM5C sensitizing cells to PARP7 inhibition.

The therapeutic success of CAR-T cells depends on the availability of selective and high-density targets, which limits their applicability due to on-target off-tumor toxicity. Here authors overcome this limitation in a mouse model of immune therapy in which an adaptor is an epitope-tagged single chain variable fragment targeting the tumour antigen, and the CAR-T cells are targeting the epitope, thus enabling a precise dose-switch.

The ablation of FAS and CD3 in allogeneic chimeric antigen receptor T cells confers them with partial protection from rejection by T cells and natural killer cells in immunocompetent hosts.

Mutations at two key positions in the TERT promoter are frequent drivers of cancer, but the role of rare, atypical mutations in this region remains unclear. Here, the authors demonstrate that atypical TERT promoter mutations develop after canonical ones due to locally elevated UV-induced DNA damage.

Intrahepatic cholangiocarcinoma (ICC) remains poorly characterised in Chinese patients. Here, the authors profile 204 Chinese primary ICCs using deep whole-exome sequencing, and propose SAV1 as a driver of ICC due to its mutation frequency and potential tumour suppressor activity.

The prostate cancer tumour microenvironment in the context of treatment remains to be explored. Here, single-cell RNA-sequencing and spatial transcriptomics analysis of samples at multiple treatment points from 120 patients suggests that club-like cells may contribute to treatment resistance.

The mechanisms allowing early disseminated cancer cells colonize other tissues remain largely unknown. Here, authors show that GPRC5A axis drives esophageal squamous cell carcinoma lung seeding and metastasis, in a mechanism resembling trophoblast behavior during embryo implantation.

Metabolic reprogramming is crucial for cancer progression. Here, the authors show that the high mobility group A1 (HMGA1) promotes colorectal cancer (CRC) in a AOM/DSS-induced mouse model, by enhancing lipid synthesis via upregulation of fatty acid synthase (FASN), and inhibiting FASN reduces tumor growth, suggesting potential therapeutic avenues.

The role of non-cancer cells infected by oncolytic viruses (OV) in cancer regression remains elusive. Here the authors engineer OV-sensitive and OV-resistant cancer cell lines and show that OV infection of non-cancer cells can elicit effective antitumour immunity via enhancing DC function and CD8⁺ T cell activation.

Self-propelling micro/nanomotors represent a therapeutic option for drug delivery. Here the authors report the design and characterization of a biodegradable urease-powered nanomotor containing STING agonist, promoting anti-tumor immune responses in bladder cancer models.

Shimada et al. show that uncoordinated repair by base excision repair generates a lethal accumulation of DNA double-strand breaks at clustered lesions. Rapid conversion of oxidative DNA damage into fragmented chromosomes stems from TORC2 inhibition.

Predicting gene alterations and expression from whole-slide images (WSIs) can be a cost-efficient solution for cancer profiling. Here, the authors develop SEQUOIA, a transformer model with linearised attention to predict gene expression from WSIs, and validate its performance and clinical utility across multiple pan-cancer datasets.

Accurately detecting cancer mutational profiles from circulating tumour DNA (ctDNA) remains a challenging task. Here, the authors develop MisMatchFinder, an algorithm that can detect mutational signatures in shallow whole-genome sequencing data from ctDNA across multiple cancer types.

Yu and colleagues present a single-cell transcriptomic landscape of olfactory neuroblastoma, characterizing different tumor subtypes and cancer cell responses to drug treatments.

Detecting lung cancer metastasis efficiently is crucial to improve survival. Here, the authors use single-cell RNA-sequencing and liquid chromatography mass spectrometry, analyzed by dynamic network biomarker algorithm and neural networks, to identify biomarkers of lung cancer site-specific metastasis from serum samples and primary lesions, allowing the prediction of metastatic sites and trajectories.

Multiple types of DNA damage can lead to mutations in normal cells, ultimately contributing to the development of cancer. Here, the authors redefine the spectrum of mutational signatures linked to a particular type of DNA damage to uncover the protective role of specialized DNA repair mechanisms.

Monitoring of minimal residual disease is a key method for detecting potential acute myeloid leukaemia relapse. Here, the authors developed a longitudinal mutation burden monitoring strategy using ultra-sensitive mutation sequencing to quantitate VAF below 0.01% for accurate minimal residual disease assessment and relapse prediction.

We evaluated the use of chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) for H3K27M⁺ diffuse midline glioma (DMG), finding that intravenous administration of GD2-CART, followed by intracranial infusions, induced tumour regressions and neurological improvements in patients with H3K27M-mutant pontine or spinal DMG.

The underlying mechanisms for drug resistance in Acute Myeloid Leukemia (AML) are not completely understood. Here, the authors show that succinate accumulation, associated with succinate dehydrogenase deficiency, impairs the activity of the ubiquitin-conjugating enzyme UBC12 leading to tumor-promoting protein accumulation and drug resistance in AML.

FastGlioma is a visual foundation model for fast and accurate detection of glioma infiltration in fresh, unprocessed surgical tissue.

Responses to immune checkpoint inhibitors in patients with pancreatic ductal adenocarcinoma (PDA) remain low and alternative combinatorial approaches are warranted. Here the authors report the results of a phase 2 clinical trial of entinostat (histone deacetylases inhibitor) and nivolumab (anti-PD-1 inhibitor) in patients with metastatic PDA.

AI models can extract clinical outcomes from electronic health records, but it is critical to ensure that such models preserve patient privacy. Here, the authors develop a teacher-student approach to produce shareable models for annotating cancer outcomes from imaging reports and oncologist notes while protecting patient privacy.

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.

Recent progress in understanding senescence has spurred interest in the development of approaches that target senescent cells. This Review assesses the current status of senotherapies, such as senolytics and senomorphics, how these approaches can be combined with cancer therapies, and the challenges and opportunities in moving senotherapies to clinical practice.

In this Review, the authors provide an overview of molecular imaging in renal cell carcinoma, discussing the role of molecular imaging approaches in renal cell carcinoma diagnosis, treatment and response monitoring.

A common germline missense-encoding polymorphism in HSD3B1, called the adrenal-permissive allele, facilitates androgen synthesis from adrenal precursors via increased 3β-hydroxysteroid dehydrogenase 1 (3βHSD1). Here, the authors focus on mechanistic and clinical investigations of 3βHSD1 and the clinical consequences and potential utility of detecting adrenal-permissive allele inheritance.

Recent clinical trials testing CAR T cells on solid tumors have yielded promising outcomes that can be enhanced with further CAR engineering.

Defects in the DNA damage response have been utilized therapeutically for cancer for a decade. This Review analyses the lessons learnt from the development of PARP inhibitors and how these may be applied to new targets to maximize success. Targeting multiple DNA damage response pathways simultaneously and combinations with other therapies are also discussed.

In this Review, Wang and Zhang summarize the major findings of genetic and epigenetic association studies performed on cohorts of survivors of childhood cancer, which provide insights into the long-term adverse effects related to cancer therapy, and present suggestions for a future survivorship research strategy to inform precision survivorship care.

This Review details the use of multifunctional magnetic nanoparticles in advanced magnetic imaging modalities and therapeutic hyperthermia. The potential of magnetic nanoparticles for imaging-guided precision heating of tumours and the need for integrated magnetic imaging and heating platforms are highlighted.

In several B cell malignancies, BTK is a crucial mediator of oncogenic signalling pathways and inhibitors of this kinase have substantially improved patient outcomes. This Review discusses the currently approved indications for covalent and non-covalent BTK inhibitors, as well as mechanisms of resistance, and novel BTK-targeted agents and treatment strategies that have the potential to further improve outcomes.

Metastatic urothelial cancer exhibits substantial molecular heterogeneity compared with the primary tumour, complicating the development of accurate biomarkers. Pre-treatment metastatic biopsies capture real-time tumour biology and can enhance response predictions for targeted therapies, improving patient selection for precision oncology.

The Cancer Dependency Map (DepMap) is a data repository and research platform that can be utilized to systematically identify cancer vulnerabilities. Here Arafeh, Shibue et al. outline the current limitations and future strategies to enhance the DepMap project.

Immunotherapy shows promise in treating cancers by engineering T cells or using antibodies to activate them. However, cancer stem cells (CSCs) resist immunotherapies and drive cancer relapse. In this Review, Agudo and Miao highlight the mechanisms through which normal stem cells and CSCs in solid tumours achieve immune resistance, offering insights for the development of more effective cancer treatments.

In this Review, Hanahan et al. discuss how, in response to tumorigenesis, nearly all cell types in the tumour microenvironment can be programmed to mediate — as functionally distinct subtypes — immunosuppressive programmes that result in the inhibition of antitumour T cell activity and the evasion of immune destruction.

Understanding the early steps of cancer development is crucial for cancer prevention. In this Review, the authors summarize the advantages and limitations of clinical samples, autochthonous mouse models and organoid models, alongside advanced techniques such as direct imaging, lineage tracing and AI, to enhance understanding of early cancer progression.

This Perspective considers present and historical paradigms of therapeutic cancer vaccines and describes a conceptual framework, termed Vax-Innate, to simultaneously generate robust tumour-specific T cell responses and remodel the suppressive tumour microenvironment (TME). The authors detail how this strategy could be achieved through systemic vaccination and by using immune modulators to improve dendritic cell and macrophage function in the TME.

Examination of racial disparities in prostate cancer in the USA and UK highlights systemic, socio-economic and sociocultural factors that might contribute to these differences. Understanding behavioural medicine might inform and improve the way in which the health-care system can engage with patients in minorities who are affected by this disease.

Multiple myeloma is a plasma cell malignancy that is currently incurable. Cordas dos Santos et al. describe how multiple myeloma arises from precursor states and how T cell-redirecting therapies might be used to intercept disease progression at these earlier stages to improve patient outcomes.

Single-cell epigenomic technologies are refining our understanding of cancer evolution. Here Laisné et al. describe how epigenomic heterogeneity generates dynamic reservoirs of tumour cell states, through epigenomic reprogramming and selection among stochastic changes, which can be leveraged in the design of novel therapies.

In this Review, Rabas et al. describe the mechanisms by which primary tumours precondition distal organs to favour metastatic colonization — a limiting step of metastasis — and discuss how non-cancer-dependent perturbations of tissue homeostasis are also able to trigger pro-metastatic conditioning, emphasizing the need for a holistic view to identify preventive or therapeutic opportunities.

In this Review, Linke, Munn and Jain provide a framework for understanding solid stress mechanobiology, examine the emerging and diverse roles of elevated compressive stresses in solid tumours, and highlight the potential for targeting mechanical abnormalities in cancer.

Although splicing factors are altered in cancer through mutations and copy number variations, their exact role remains challenging to define. In this Roadmap, Anczukow, Thomas-Tikhonenko and colleagues explore recent advances in splicing biology and provide guidance on leveraging these insights to facilitate the clinical application of compounds that target or exploit aberrant splicing patterns in cancer.

Feedback mechanisms between androgen and IGF1 signalling pathways have been linked to the development, progression and hormone refractoriness of prostate cancer. In this Review, the dynamic regulation of androgen and IGF1 signalling in prostatic epithelia and stroma are described and the implications for future preventative and therapeutic strategies are explored.

In this Review, Crawford and Turocy examine diverse small molecule metabolites produced by the human microbiota, their role as potential risk factors for cancer development as well as novel mechanistic insights demonstrating their association with gastrointestinal cancer.

In this Review, Shay and Yilmaz describe how diet and metabolism influence intestinal stem cells in health and disease, including tumorigenesis. The effect of dietary changes such as calorie restriction, intermittent fasting, high-fat diets and ketogenic diets on intestinal stem cells is discussed.

In this Comment, Ben-Aharon et al. advocate for the creation of designated OncoYoung programs to address the unique needs of individuals with early-onset cancer, as well as multinational platforms with dedicated funding to investigate the aetiology of this disease and to develop preventive measures.

Despite extensive advancements in cancer genetics in North America and Europe, the African continent remains underrepresented in this vital research area. Here we highlight a pioneering collaborative project in Kenya, with a focus on expanding cancer genetics services and research into retinoblastoma, a prototypical heritable cancer syndrome.

The I-SPY clinical trial platform was designed to accelerate clinical development of neoadjuvant treatments for early-stage breast cancer. Although it is not without limitations, it provides a model for future response-adapted clinical trials.

Virologist Beata Halassy says self-treatment worked and was a positive experience — but researchers warn that it is not something others should try.

The occurrence of multiple independent tumours in patients with EGFR-mutant lung cancer was unexplained. A recent study in Nature Cancer identified distinct genetic predisposition mechanisms, including developmental mosaicism and germline EGFR variants, that contribute to the formation of multiple primary tumours.

Some bacteria can cause mutations associated with colon cancer. Insights about the surface adhesion proteins that enable these bacteria to bind to host cells point to how steps leading to tumour formation might be halted.

Engel et al. conducted a genetic screen in which they identified the Fanconi anaemia (FA) pathway as a driver of chromothripsis, complex genomic rearrangements and generation of extrachromosomal DNA.

The DESTINY-Breast06 trial investigated earlier and broader use of trastuzumab deruxtecan in patients with metastatic hormone-receptor-positive breast cancer, and demonstrated improvements in progression-free survival over standard chemotherapy. These data provide a meaningful advance; however, this strategy might not be right for all patients, and careful consideration is recommended before blanket use.

A number of therapeutics that target mediators of signalling in the hypothalamic and brainstem regions that control appetite, ingestive behaviour, satiety, nausea and vomiting are starting to move the needle on cancer cachexia. However, clarification of meaningful clinical benefits for patients and the primary end points that should support regulatory approval of cachexia treatments is needed.

Ageing is a well-accepted risk factor for developing cancer. Yan et al. used a preclinical rat model to study the mechanisms facilitating the age-associated increase in breast tumorigenesis.

The early molecular events driving cancer initiation remain elusive, hampering prognostic accuracy. A comparative analysis of 3D genomics data from all stages of colon malignant transformation now reveals that altered connectivity of gene promoters with cognate enhancers is both predictive of and rate-limiting in neoplasia.

Cancer-cell-derived extracellular vesicles bind to therapeutics and shuttle them out of the tumour to the liver for destruction.

Charting the evolution of cancer at single-cell resolution could open up avenues for early diagnosis and treatment.

The isolation of the BRCA1 gene 30 years ago ushered in the era of genetic testing for breast and other cancers, launched a long-lasting patent battle and eventually led to a tailored cancer therapy.

Liquid–liquid phase separation has been shown to be involved in tumorigenesis. Phosphorylated HDAC6 is now found to form nuclear biocondensates that affect chromatin conformation and thereby gene expression, contributing to malignancy in triple-negative breast cancer.

Tertiary lymphoid structures (TLS) have different stages and cellular compositions in human tumors. New data are showing the effect of neoadjuvant immunotherapy on the fate of TLS in treatment-responsive versus treatment-resistant liver cancers.

Adjuvant chemoradiotherapy has a proven survival benefit for patients undergoing upfront resection of gastric cancer compared with surgery alone. Now, data from the TOPGEAR trial demonstrate that adding radiotherapy to standard-of-care perioperative chemotherapy offers no additional survival benefit. I discuss the implications for treatment and future research.

A large study failed to show a reduction in gastric cancer incidence or mortality when Helicobacter pylori screening was added to standard colon cancer screening.

In the NIAGARA trial, the addition of perioperative durvalumab to standard treatment for muscle-invasive bladder cancer improved event-free and overall survival, marking a new treatment option for this condition.

CAR-T cells are revolutionizing the treatment of cancer and other diseases. A latest iteration in development involves fusion with an antigen-based CAR enhancer to provide low-affinity IL-2 signaling that might limit adverse effects.

In this Tools of the Trade article, Siyu He describes the development of Starfysh, a computational toolbox that integrates histology of complex tissues in spatial transcriptomic data analysis to characterize cell states.

We developed NeoDisc, a computational antigen discovery pipeline that integrates multi-omics data, including genomics, transcriptomics and mass spectrometry-based immunopeptidomics. NeoDisc accurately identifies and prioritizes tumor-specific antigens and designs personalized cancer vaccines. The pipeline reveals tumor heterogeneity and emphasizes defects in antigen presentation that might affect the success of cancer immunotherapy.

In a recent study published in Cell, Chhabra et al. identify age- and sex-dependent changes in skin fibroblasts that drive melanoma aggressiveness, with aged male fibroblasts promoting a slow-cycling, invasive state and resistance to targeted therapy in melanoma cells.

Akiko Takahashi discusses the seminal 1997 paper by Serrano et al. who found that oncogene activation results in a similar phenotype to replicative senescence, establishing the connection between senescence and cancer.

Aging is associated with biological processes (such as the accumulation of senescent cells) that are relevant to the development of cancer. Using genetically modified mouse models, we discovered that p16^high senescent cells with a secretory phenotype accumulate in the bladder during aging, which leads to cancer progression.

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.