Review Articles

Radiation therapy induces immune responses both systemically and within the tumour microenvironment. In this Review, Darragh and Karam present preclinical and clinical evidence to highlight this complex interplay and outline strategies to enhance the immunogenic potential of radiation therapy to improve both therapeutic efficacy and patient outcomes.

Pancreatic ductal adenocarcinoma is defined by a fibroinflammatory microenvironment, which influences both disease progression and therapy response. In this Review, Arnold et al. outline our current understanding of the complex interplay between the stromal elements of the tumour microenvironment in pancreatic ductal adenocarcinoma and present ways we might use this knowledge to develop better therapeutic strategies for patients with pancreatic cancer.

Artificial intelligence agents are autonomous systems that use large language models to reason and as such can perform complex, multistep tasks with minimal human oversight. This Review by Truhn et al. discusses how these agents — which have already been implemented in several industries — could transform cancer research and oncology, and looks at the challenges that need to be addressed before they can be efficiently and safely used.

In this Review, Lu et al. discuss the dual role of the cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS)–stimulator of interferon genes (STING) pathway in cancer, emphasizing its involvement in both tumour suppression and promotion. They highlight the diverse sources of pathway activation and suggest that this functional duality may underlie the limited clinical success of cGAS–STING targeting in cancer therapy.

Macrophages can eliminate cancer cells through phagocytosis, which is tightly regulated through inhibition and activation of various phagocytic receptors. In this Review, Veillette and colleagues outline how targeting these phagocytic checkpoints could be harnessed therapeutically, address therapeutic efficacy concerns, and propose strategies to enhance therapeutic outcomes in future clinical applications.

In this Review Luo, Kharas and Jaffrey outline how N⁶-methyladenosine (m⁶A) RNA modification affects RNA stability, translation, splicing and immune responses to influence cancer biology. They discuss emerging evidence on how m⁶A may influence cancer metabolic reprogramming and outline the challenges and opportunities of targeting m⁶A writers, erasers and readers for cancer therapy.

Concomitant medications are emerging as a modifiable prognostic factor for immune checkpoint inhibitor treatment outcomes. This Review by Stone et al. highlights the potential immunomodulatory interactions of commonly prescribed medications and supplements, and proposes strategies to make better use of this information to guide clinical care.

Tumour heterogeneity has a substantial impact on tumour progression and treatment response, yet bulk expression data obtained from clinical tumour samples obscure this complexity. Computational deconvolution methods can resolve cell-type-specific signals. This Review offers a practical guide for cancer researchers to select deconvolution methods and maximize the utility of bulk transcriptomic data.

Macropinocytosis enables cancer cells to absorb nutrients from their environment, supporting growth and therapy resistance. In this Review, Tang, Wang, Kroemer and Kang outline its regulatory mechanisms, implications for treatment strategies and potential as a target for enhancing therapeutic efficacy in oncology.

Neutrophil extracellular traps (NETs) influence cancer initiation, progression and metastasis through immunosuppressive mechanisms within the tumour microenvironment. In this Review, Shahzad et al. highlight our recent understanding of NET biology in cancer and emphasize both the translational data available and the need for further clinical trials evaluating NETs and NET-directed therapies.

Transcriptional and epigenetic mechanisms governing T cell exhaustion substantially impact immunotherapy effectiveness. In this Review, Kang et al. outline epigenetic regulatory programmes that influence T cell differentiation fates, proposing strategies to enhance clinical outcomes and immunotherapy durability in cancer through improved understanding of T cell biology.

In this Review, Mao et al. discuss the regulation and interplay of the metabolic cell death pathways ferroptosis, disulfidptosis and cuproptosis and explore how these mechanisms can be harnessed for cancer therapies.

Although ferroptosis, an iron-dependent form of regulated cell death, is emerging as a therapeutic vulnerability in cancer, clinical translation is hindered by context-dependent regulation, a lack of predictive biomarkers and challenges in clinical trial design. In this Review, Wahida and Conrad examine the biological basis of ferroptosis, including its immunogenic potential, and outline the necessary steps towards translating ferroptosis-based therapies into the clinic.

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.