Megakaryocytes contribute substantially to the pathogenesis of myeloproliferative neoplasms (MPNs), but therapeutic strategies targeting this lineage are lacking. Wen, Cotton et al. demonstrate that menin inhibition impairs megakaryocyte differentiation, suppresses myelofibrosis and improves disease features across preclinical MPN models.
Many advances in cancer treatment depend on discoveries made decades earlier. In this Comment, Murphy et al. discuss the histories of EGFR, HER2, CDK4/6 and RAS, highlighting how long translation can take and how clinical benefit can continue to accumulate as more effective drugs are developed, used in earlier disease settings and combined with existing treatments.
Immunotherapies have substantially advanced cancer treatment; however, their efficacy in gliomas remains limited. This observation cannot be fully explained by tumour-intrinsic factors and may rather be linked to the distinct relationship between the central nervous system (CNS) and the immune system, commonly described as CNS immune privilege. CNS immune privilege is maintained by specialized brain barriers that divide the CNS into compartments with distinct accessibility to immune mediators and immune cells. Although maintaining homeostasis of the CNS parenchyma, these brain barriers direct CNS immune surveillance to the subarachnoid and the perivascular spaces at the CNS borders. Consequently, tumours arising in the CNS parenchyma are shielded from effective immune detection, limiting the efficacy of immunotherapies such as immune checkpoint inhibitors, cancer vaccines and adoptive T cell therapies such as chimeric antigen receptor (CAR) T cells and T cell receptor (TCR) transgenic T cells by restricting their access. Importantly, emerging evidence also indicates that gliomas actively remodel brain barrier functions to reinforce immune evasion. Failure to adequately consider brain barrier function in the context of immunotherapy strategies and clinical trial design therefore represents a major gap in the field. Understanding the orchestrated function of the brain barriers as neuroimmunological interfaces is essential for enhancing immune surveillance and improving immunotherapy responses in patients with brain tumours.
In this Journal Club, Sandra Romero-Cordoba discusses a study that identifies a replication-associated DNA methylation signature, termed CellDRIFT, providing evidence that epigenetic drift linked to cell division may contribute to oncogenic transformation.
The progression of pancreatic ductal adenocarcinoma (PDAC) from precursor lesions presents an opportunity for cancer prevention. Haldar et al. developed mKRAS-VAX, a peptide vaccine targeting six common KRAS mutations in PDAC, and evaluated it in a phase I clinical trial.
No existing model can reliably predict how an individual cancer will evolve. The future of precision oncology lies not in increasingly sophisticated in vitro tumour models or in artificial intelligence alone, but in the iterative feedback loop between the two. No existing model can reliably predict how an individual cancer will evolve. In this Comment, Guimarães and Reis argue that the future of precision oncology lies not in increasingly sophisticated in vitro tumour models or in artificial intelligence alone, but in the iterative feedback loop between the two.
Tian et al. conducted an observational cohort study utilizing data from biobanks in the UK and USA, finding that more advanced biological ageing compared to chronological age may be a risk factor for early-onset solid cancers with implications for cancer prevention and early interception.
Gasdermins (GSDMs) are a family of pore-forming proteins that execute pyroptosis, a lytic form of programmed cell death associated with membrane rupture. This function of GSDMs was initially identified from studies of gasdermin D (GSDMD), which is cleaved and activated by inflammatory caspases in the inflammasome pathway. It is now established that other eukaryotic or pathogen-encoded proteases, as well as post-translational modifications, can also activate GSDM family members independent of inflammasomes and in multiple cell types including cancer cells. T cell granzyme-mediated GSDM activation, exogenous delivery of active GSDMs, and small molecule-induced activation of GSDMs in cancer cells have been shown to promote antitumour immunity through pyroptosis. Notably, only a fraction of cancer cells needs to undergo pyroptosis to induce immune cell infiltration and antitumour immunity with tolerable toxicity. Here, we summarize current knowledge on the role of pyroptosis in antitumour immunity, discuss pyroptosis in the context of other lytic forms of cell death, and provide an outlook on how cancer cell pyroptosis may synergize with existing immunotherapies.
In this Journal Club, Muñoz-Bello and Lizano discuss the discovery of circE7, a protein-coding circular RNA generated by back-splicing in high-risk HPV that drives E7 expression and tumour growth, revealing a previously unappreciated mechanism of viral oncogene regulation.
Glioblastoma exhibits sex-specific differences in disease progression, incidence and immune regulation. Now, Pathak et al. identify GABA (γ-aminobutyric acid) as a key driver of granulocytic myeloid-derived suppressor cell-mediated glioblastoma progression in women.
In a recent study, Lei, Lu, Xu et al. identify cuproptosis as a form of immunogenic cell death that stimulates adaptive antitumour immunity. In turn, CD8⁺ T cell-derived IFNγ enhances tumour sensitivity to cuproptosis through STAT1–IRF1–FDX1 signalling, establishing a reciprocal immunometabolic circuit with important implications for cancer immunotherapy.
A recent study identifies TEX264-dependent nucleophagy as an important mechanism that mediates the clearance of trapped PARP1, thereby limiting PARP1-induced toxicity and promoting resistance to PARP inhibitors.
Acute lymphoblastic leukaemia (ALL) is characterized by uncontrolled proliferation of lymphoid progenitor cells. Advances in genomic and epigenomic profiling have enabled the identification of over 40 molecular subtypes defined by distinct genetic drivers, transcriptional programmes and regulatory alterations. These insights have refined the classification, particularly of B cell precursor ALL (B-ALL) and are increasingly informing risk stratification, therapeutic decision-making and disease monitoring. By contrast, the classification of T cell ALL (T-ALL) has historically relied on immunophenotypic criteria, but recent large-scale genomic studies have uncovered biologically defined subtypes driven by diverse coding and noncoding alterations. Many genomic lesions represent clinically actionable vulnerabilities, including kinase-activating alterations that have enabled the use of targeted therapies. However, treatment resistance remains a major challenge, arising through clonal evolution, acquisition of secondary mutations and adaptive transcriptional and epigenetic reprogramming. In this Review, we highlight recent advances in understanding of the biological basis of ALL, with a focus on recently identified genetic alterations, gene expression patterns, alterations in three-dimensional genome architecture and epigenetic regulation that drive ALL initiation, progression and therapeutic response. Furthermore, we discuss how genetic heterogeneity contributes to clinical variability and how integrating molecular and biological insights can improve risk stratification and therapeutic outcomes.
Cancer is a systemic disease that perturbs the homeostasis of host tissues and organs, exerting manifestations both locally and distantly. Extracellular vesicles and particles (EVPs) have a pivotal role in intercellular communication between tumours and the host by transferring bioactive cargo to recipient cells, contributing to the systemic effects of cancer. Tumour-derived EVPs prepare distant organs for future metastasis, by creating a pre-metastatic niche (PMN). Additionally, tumours manipulate multiple organ systems to support their growth and evade immune detection. This co-option of host systems leads to cascading dysfunction across multiple organs, ultimately compromising host survival. Here we review the diverse systemic impact of cancer-associated EVPs, including immune dysregulation in PMNs, thrombosis and cardiovascular disease, liver metabolic dysfunction, glucose metabolism disorders, cachexia, and paraneoplastic syndromes of the nervous system. Furthermore, we discuss the intricate communication between host-, diet- and microbiota-derived EVPs and cancer cells, highlighting the complex interplay mediated by these EVPs in cancer progression and anti-cancer treatment responses. We also explore the prospects of EVPs as a systemic therapeutic approach for anti-cancer treatment. Overall, this Review highlights the need to address the systemic effects of cancer and to adopt holistic approaches to cancer treatment, by simultaneously targeting the tumour and its multi-organ paraneoplastic effects. These strategies hold great promise in mitigating the broad impact of disease progression and comorbidities and ultimately improving the quality of life and survival of patients.
In this Tools of the Trade, Weiwei Hu describes the development and use of CLIM-TIME, a scalable in vivo platform that integrates CRISPR perturbation screens with spatially resolved transcriptomic and immune profiling to link tumour-intrinsic genetic alterations to distinct immune microenvironments.
The hallmarks of cancer were introduced by Hanahan and Weinberg as a conceptual organizing framework to distil the complexity of tumours. This concept of cancer hallmarks has become an enduring theme in cancer research. Moreover, an increasing number of therapeutic strategies are being aimed at targeting these hallmarks. However, translating them into the clinic requires technologies to monitor their effectiveness and biomarkers that can stratify patients for the choice of specific therapies. Tumour heterogeneity and the ability of tumour cells to rapidly mutate and develop evasion strategies makes the development of non-invasive imaging capabilities to interrogate these hallmarks as biomarkers and monitor them longitudinally and quantitatively particularly important. This Review presents a holistic discussion of non-invasive diagnostic imaging capabilities related to the hallmarks of cancer; some hallmarks can be assessed with imaging probes that directly target biomolecules, whereas others can be interrogated indirectly by imaging pathophysiological processes. Additionally, visualizing the hallmarks of cancer can be addressed with artificial intelligence-assisted, multiparametric image analysis (for example, radiomics, radiogenomics and deep learning). The approaches discussed have been evaluated in a translational context, and some of them already have a substantial role in clinical practice, for example, to guide treatment strategies, including surgical resections, radiotherapy and molecularly targeted chemo-, immuno- and radiopharmaceutical therapies.
Gut microbiome composition and metabolite profiles have previously been linked to both colorectal tumorigenesis and immune checkpoint inhibitor responsiveness. Now, Lobel et al. identify sulfur amino acid metabolism as a microorganism-derived metabolic pathway that enhances anti-tumour immunity.
It is crucial to know how to communicate your work by delivering an effective talk, but our training for doing so is limited, so it is a skill often learned by watching others — who sometimes do it badly. Effective presentations require clarity and audience awareness. In this Comment, Itai Yanai outlines common misconceptions about presentations and how to address them to deliver more impactful and insightful talks.
The connections between viruses and cancer have historically been studied in the context of viral oncogenesis. For decades, tumour virology has focused on oncogenic viruses such as hepatitis B virus, hepatitis C virus, human papillomavirus, Epstein-Barr virus, human T cell leukaemia virus type 1, Kaposi sarcoma-associated herpesvirus and Merkel cell polyomavirus, elucidating their oncogenic mechanisms, which include mutagenesis, chronic inflammation and immune evasion. However, the human virome is vast and complex, and this oncogenesis-centred view has overshadowed the possibility that certain viral exposures enhance antitumour immunity. Through millions of years of coevolution with animal hosts, the virome, consisting of diverse bacteriophages and eukaryotic viruses, including endogenous retroviruses, appear to have evolved strategies for coexistence that shape immune development and potentiate host surveillance pathways capable of recognizing and eliminating cancer cells. Non-oncogenic viruses can prime innate and adaptive immune responses, mimic tumour antigens and modulate the expression of immune checkpoints, as exemplified by the association of the enterovirus and rhinovirus CE1 epitope with protective liver cancer immunity. Moreover, endogenous retroviruses, naturally occurring oncolytic viruses and microbiome-associated phages may act as allies in cancer control. This Review explores the emerging evidence for viral anticancer immunity, its underlying mechanisms, and implications for a virome-guided framework for cancer prevention including new approaches to risk assessment, immune-based therapeutics and applications in low-resource settings.
