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.

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.

Human tumours consist of highly heterogeneous and interacting cell types organized within a complex 3D space, forming a dynamic ecosystem that evolves through the development of pre-malignant lesions, tumour initiation, progression, invasion and metastasis. Understanding the operational principles of tumour evolution at a holistic 3D level is critical for improving the ability to intercept and treat cancer early. Emerging technologies in spatial multi-omics and the generation of 3D tumour atlases are beginning to address this critical need. These efforts aim to capture the intricate interactions within precancerous lesions, tumours and their surrounding ecosystems over space and time. In this Review, we highlight emerging tools developed within and beyond the tumour atlas community and explore their potential in constructing comprehensive 3D tumour atlases. Such atlases have the potential to reveal novel biomarkers for risk stratification, early detection, preventive intervention, and transformative diagnostic and treatment strategies. Furthermore, a 3D tumour atlas can generate new insights into the molecular and cellular mechanisms driving human tumour evolution, paving the way for future research and innovation in cancer biology.