Reviews & Analysis

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.

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.

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.

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.

Fifty years ago, Köhler and Milstein introduced the world to hybridoma technology for the generation of monoclonal antibodies. Scientists have subsequently built upon this seminal discovery to develop antibody-based therapies for numerous diseases, with millions of patients benefiting from such drugs. To mark 50 years of monoclonal antibodies, this Review from Chan, Martyn and Carter provides an overview of how antibody engineering strategies have continued to improve antibody-based therapeutics, chiefly focusing on antibody-mediated targeting of B cells and also human epidermal growth factor receptor 2 (HER2)⁺ cancers. The authors also highlight the promise of emerging tools, including artificial intelligence, for development of the next generation of antibody-based therapeutics.

Modification of the nucleotide pool is emerging as key to innate immunity in animals, plants and bacteria. This Review explains how immune pathways conserved from bacteria to humans manipulate the nucleotide pool to block viral replication and produce immune signalling molecules.

This Review by Poirier highlights the intrinsic mechanisms that protect stem cells from infection. The author also explains how stem cell populations in different tissue sites respond to infection or injury to protect tissue integrity, and the impact of inflammageing on these processes.

Endometritis can cause infertility and recurrent pregnancy loss and is an important medical and veterinary issue. Here, Nash and Giles provide an overview of the various models that can be used to study uterine inflammation and discuss their value for developing new therapies.

Here, Swirski and colleagues explore how the nervous and immune systems connect and collaborate to respond to internal and external stimuli. In particular, they consider how the exchange of information between both systems is vital for host physiology, in the context of both health and disease.

The vasculature that forms in tumours and supports tumour growth is abnormal and limits T cell entry into tumours. Here, the authors review how the tumour vasculature acts as a barrier to effective antitumour immunity and the therapeutic strategies to overcome this.

In this Review the authors explain how different routes of exposure to food antigens can contribute to the development of food allergies. They discuss how allergic sensitization occurs against food antigens and focus on how IgE and mast cells ultimately drive the allergic pathology.

During pregnancy, innate immune mechanisms at the maternal–fetal interface are important for protecting the developing fetus from pathogens. However, excessive immune activation can be harmful to the fetus, and these pathways must be properly regulated. Here, the authors discuss the growing understanding of the unique innate immune pathways that operate in the maternal and fetal compartments of the placenta.

Iron is crucial for cellular metabolism, but its availability varies greatly within and between individuals and populations. This Review highlights how iron regulates innate and adaptive cellular and humoral responses affecting protection against infections, tumours and autoimmunity.

T cells have an essential role in immune responses to Mycobacterium tuberculosis, but the mechanisms by which they may provide protective immunity remain poorly understood. This Review explores the knowns and unknowns of T cell immunity in tuberculosis and how recent technologies may inform the design of T cell-targeted TB vaccines.

This Perspective explores how the gut microbiota influences the function and heterogeneity of microglia, highlighting their roles in neurological and neuropsychiatric disorders, and discusses the therapeutic potential, challenges and clinical implications of targeting microbiota–microglia interactions.