The DNA damage response (DDR) and immune system serve as critical defence mechanisms, safeguarding genomic integrity and providing host protection, respectively. Emerging research reveals their interconnection in dictating the response to cancer immunotherapy. DDR-deficient tumours or those exposed to DDR inhibitors display genomic instability that generates two key immunogenic signals: neoantigens that activate tumour-specific T cells; and cytosolic DNA that stimulates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, triggering type I interferon production and immune cell recruitment. These synergistic effects drastically enhance responsiveness to immune checkpoint blockade. This Review examines the molecular mechanisms by which DDR defects potentiate immunotherapy, including recent advances in DDR-targeted combination strategies. We further analyse resistance mechanisms and discuss innovative approaches to overcome therapeutic limitations, offering a comprehensive perspective on exploiting DDR deficiencies for improved cancer treatment outcomes.

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.

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.

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.