Articles in 2025

The tumour microenvironment (TME) poses a significant obstacle to the success of chimeric antigen receptor (CAR) T cell immunotherapy in solid tumours. Here, the authors detail how both cellular and non-cellular components of the TME contribute to tumour resistance against CAR T cell therapy, and explore emerging strategies aimed at overcoming these barriers in order to enhance the efficacy of CAR T cell therapy.

In this Review, the authors discuss the latest advances in our understanding of organelle biology in T cell-mediated antitumour immunity and how this knowledge is being used to power the next generation of cancer immunotherapy applications through pharmacological or genetic manipulation of organelles and intercellular organelle transfer or organelle transplantation.

Amyotrophic lateral sclerosis is associated with CD4⁺ T cells that are specific for the C9orf72 autoantigen and preferentially produce IL-4, IL-5 and IL-10.

Group 2 innate lymphoid cells are crucial for maintaining nerve structure and pain thresholds.

A proteotoxic stress response specific to exhausted T cells represents a target for cancer immunotherapy.

Depending on context and concentration, the polyamine cadaverine can promote pro- or anti-inflammatory macrophage polarizations.

This Review explains how an improved understanding of immune and nervous system interactions in the central nervous system (CNS) has guided the use of immunotherapies (including chimeric antigen receptor T cells, oncolytic viruses, cancer vaccines and immune-checkpoint inhibitors) to treat CNS tumours. The authors highlight the outcomes of clinical trials that have used immunotherapy to treat primary brain cancers and provide a perspective on future directions for the field.

A study in Science Immunology reports that regulatory T cells in the skin modulate neuronal tone directly through their production of the opioid enkephalin.

Here, Sun and Dong describe the many signals from stimulatory and inhibitory molecules as well as by microenvironmental factors, such as cytokines, metabolites and neuronal factors, that regulate CD8⁺ T cell exhaustion. They explain how these extrinsic factors reshape the T cell transcriptome, epigenome and metabolism towards a state of exhaustion through intrinsic cell regulators.

Many patients with cancer who could potentially benefit from treatment with chimeric antigen receptor (CAR)-T cells do not have access to this therapy. This Comment explores the unique barriers to a broader clinical adoption of CAR-T cell therapy and propose new routes to improve timely and equitable access to treatment.

Neoadjuvant (chemo)immunotherapy has become a new standard-of-care option for patients with cancer. This Perspective discusses the lessons learnt for neoadjuvant immunotherapy in the context of melanoma and where the field is heading next, particularly an increased understanding of the role of immune education in therapy resistance and the need for biomarker-driven therapy personalization to uncouple toxicity from efficacy.

Despite the advances in hepatitis C treatment, a prophylactic vaccine is still not available and will be needed to control and eliminate hepatitis C virus (HCV) infections globally. In this Review, the authors examine the current understanding of protective immune responses and describe the challenges, prospects and new technologies in HCV vaccine development.

The actin cytoskeleton is essential for immune cell shape, signalling and function. In this Review, the authors examine how germ-line mutations affecting actin-regulatory proteins, called immune-related actinopathies, lead to inborn errors of immunity. These are characterized by susceptibility to infection as well as autoimmune and autoinflammatory disease manifestations. Focusing on WASP, HEM1 and DOCK11 deficiencies, the authors examine the diverse mechanisms that link disturbed actin homeostasis in lymphoid and myeloid cells to autoimmunity and autoinflammation and outline emerging mechanistic insights and therapeutic directions.

Functional and metabolic properties of innate-like T cells — namely, iNKT cells, MAIT cells and some γδ T cells — differ from those of conventional T cells. This Review describes how metabolic pathways support innate-like T cell properties such as acquisition of effector capability in the thymus, rapid responsiveness, tissue persistence, antigen adaptation and functional flexibility.

The dual nature of non-polymorphic MHC-E as a ligand for innate receptors and as an antigen-presenting protein raises the possibility of new, universally effective vaccines and immunotherapies for infectious disease and cancer that are independent of the MHC haplotype of an individual.

Populations of regulatory KIR⁺CD8⁺ T cells expand during pregnancy and can promote maternal tolerance to the developing fetus.

B cells that expand following infection with EBV can colonize the brain, where they recruit activated T cells that have potential to cause neuronal damage, thereby providing a mechanism to explain the link between EBV and increased MS risk.

A study by Bhattarai et al. in Nature Immunology reports that ILC3-to-ILC1 plasticity in the gut is regulated by circadian clock proteins.

Tumour-associated blood vessels are abnormal in structure and function, and this can limit immune cell infiltration into tumours and contribute to the immunosuppressive tumour microenvironment. This Review highlights how tumour angiogenesis impacts antitumour immunity and explains why combining anti-angiogenic strategies with immunotherapies could improve clinical outcomes for patients with cancer.

Effective tumour-specific T cell immunity — and the success of cancer immunotherapies — relies on the presentation of antigens via human leukocyte antigen (HLA) molecules. In this Review, Bassani-Sternberg and Huber explore recent advances in understanding the repertoire of tumour-specific antigens, as well as how disruptions in antigen processing and presentation contribute to immune evasion and resistance to immune checkpoint blockade. The authors also highlight how these insights can inform the design of personalized neoantigen-based vaccines and combination therapies aimed at outpacing tumour immunoediting.