Review Articles

Antibody–drug conjugates are rapidly expanding both in the clinical treatment of cancer and in preclinical development. In this Review, Zippelius et al. highlight the molecular interactions and immune system effects of these sophisticated drugs that drive their efficacy and toxicity.

In this Review, Dong and Blanpain outline our current understanding of the epithelial-to-mesenchymal transition in cancer, which we now know is not a simple binary switch but the existence of a series of different tumour states. The authors also discuss the implications of this knowledge for pharmacologically targeting epithelial-to-mesenchymal transition to overcome therapy resistance.

In this Review, Kennel and Greten highlight the role of immune cells in colorectal cancer (CRC) development, progression and metastasis as well as the impact of therapies on the immune microenvironment. They emphasize the need for novel strategies to enhance immunogenicity and CRC patient stratification to improve outcomes.

Neurotoxicity impacting the central and peripheral nervous systems is a considerable adverse effect of both conventional and novel cancer therapies. In this Review, Karschnia et al. outline what is currently known about the mechanisms that underlie the clinical symptoms of central nervous system injury and peripheral neuropathy and the ongoing development of interventions to treat and prevent this unmet medical need.

In this Review, Easwaran and Weeraratna outline how ageing leads to epigenetic alterations in the tissue microenvironment, enhancing clonal expansion of mutations and ultimately increasing cancer risk.

Ageing reshapes immune composition, function and regenerative capacity, with profound effects on tumour immunity, cancer progression and treatment outcomes. In this Review, Dolan and colleagues examine how age-resolved immunoprofiling, insights from ageing haematopoiesis and preclinical modelling are uncovering immune ageing dynamics and therapeutic challenges — revealing new opportunities to optimize cancer therapy across diverse age groups.

Ageing influences cancer risk through cellular and environmental changes, including the induction of cellular senescence. In this Review, Ye, Melam and Stewart highlight the role of senescent stromal cells in cancer and the therapeutic implications of this.

Nanoparticle surfaces can be engineered for targeted delivery of cancer therapies. In this Review, Gomerdinger, Nabar and Hammond outline the role of surface chemistry at all levels of nanoparticle trafficking, from administration route, to tissue accumulation, cellular targeting and ultimately subcellular localization. They emphasize the utility of non-covalent surface modifications for improving stealth and targeting abilities of nanoparticles for cancer.

In this Review, Parida and Malladi summarize the metabolic adaptations of tumour cells upon dissemination to the brain, outline the metabolic crosstalk between cancer and brain-resident cells and discuss potential strategies to target these adaptations to improve outcomes for patients with brain metastasis.

In this Review, Henry and DeGregori discuss the contributions of the various models and methods used to study the connection between ageing and cancer, highlighting the strengths and limitations of those models and technologies, as well as advocating for the wider adoption of age-appropriate models of cancer to improve our clinical translation of approaches to prevent and treat human cancers.

The endoplasmic reticulum (ER) has a central role in mounting effective and durable antitumour immunity. In this Review, Hwang et al. outline how tumour-induced ER stress responses alter the function of intratumoural immune cells and the efficacy of immunotherapy, highlighting the potential of unfolded protein response-targeted interventions to improve cancer outcomes.

The nervous and immune systems have co-evolved to respond to threats, including cancer. In this Review, Amit et al. outline the reciprocal interactions among neurons, immune cells and tumour cells that regulate peripheral antitumour immune responses and discuss how these mechanisms could be leveraged to enhance immunotherapy.

This Review by Imianowski et al. outlines the various contributions that regulatory T cells, present in the tumour microenvironment, make towards tumour progression and highlight the ways in which they represent attractive next-generation immunotherapeutic targets.

In this Review, Beringer and colleagues highlight how future strategies for developing immunotherapies using γδT cells and their receptors will depend on creating intentional imbalances between activating and inhibitory receptors through the genetic engineering of γδT cell-inspired biologics and cellular therapies.

Cancer prevention vaccines have reduced cancer-related mortalities, yet therapeutic cancer vaccine development and clinical translation continues to face challenges. Here, Zaidi, Jaffee and Yarchoan summarize the failures of cancer vaccines of the past, to highlight recent advancements in the field.

Targeted protein degradation (TPD) is an emerging pharmacological modality in cancer therapy. In this Review, Hinterndorfer et al. outline the mechanistic bases of TPD and discuss the characteristics, advantages and applications of established compounds as well as upcoming classes of degraders.

In this Review, Simpson et al. summarize the emergent understanding of molecular subtypes of small cell lung cancer (SCLC). They discuss how intratumour heterogeneity and dynamic tumour plasticity may challenge the success of immune and molecular subtype-targeted therapies and argue that combination therapies, monitored by serial liquid biopsy-based biomarkers, will be needed to improve the outcomes of patients with SCLC.

In this Review, Emerling and colleagues summarize the roles of phosphatidylinositol 4-kinases (PI4Ks) and phosphatidylinositol phosphate kinases (PIPKs) in cancer. They highlight the altered expression of these kinases in tumours and discuss ongoing efforts in developing therapies targeting these lesser-studied phosphoinositide kinase families.

Glucose metabolic enzymes and their metabolites provide cells with energy and building blocks for the synthesis of macromolecules. However, it has become clear that they also have non-canonical functions, which modulate various cellular activities. In this Review, Guo et al. discuss how these moonlighting functions can help drive cancer progression.

Fibroinflammation, a highly integrated fibrogenic and inflammatory response, is activated in response to tissue perturbation and thus contributes to tumour initiation, growth and metastasis. Here, Xiao and Puré outline the complexity of cancer-associated fibroinflammation and provide insights into its therapeutic targeting.