Interleukin-33 (IL-33) is an alarmin and cytokine that has potent biological effects in various tissues. It acts on a broad array of immune cell populations and is involved in many processes associated with health and disease. This Review discusses the biology of IL-33 and its receptor, ST2, and the functional relevance of IL-33-ST2 signalling. It focuses particularly on the differential regulation of IL-33 sensitivity in distinct cell types in diverse tissue settings. Furthermore, we describe the effects of IL-33 in various diseases, including viral infections, cancer, graft-versus-host disease, colitis, autoimmunity, chronic obstructive pulmonary disease, asthma and allergy. We also consider the roles of IL-33 in physiological reactions such as fat tissue biology and tissue regeneration. The Review aims to provide a comprehensive understanding of IL-33 signalling, including its potential as a target for developing new treatments, and to suggest future research directions.
Inflammation seems to permeate many aspects of our lives, with the incidence of inflammatory diseases on the rise and ageing being blamed on it. Will the next 25 years see better ways to treat or prevent inflammation and allow us to live longer and healthier lives?
Why do so many promising immunotherapies fail to reach their potential? Adrian Hayday argues that transformative clinical advances depend on protecting specialized ‘squares of discovery’ in which deep understanding and unexpected insights emerge, while building stronger pathways to biotechnology, pharmaceutical development and patient care.
Senescence, which is defined as a state of stable cell cycle arrest, can occur in all tissues of the body. The surveillance and clearance of senescent cells by the immune system is necessary for tissue homeostasis; when this immune surveillance does not occur efficiently, for example, during tumorigenesis and ageing, it has pathological consequences. For example, if the immune clearance of senescent cells is evaded, such as through recruitment of immunosuppressive cells, expression of immune checkpoint molecules by senescent cells or suppression of antigen presentation, senescent cells accumulate and lead to tissue dysfunction. Therefore, therapeutic modulation of the immune surveillance of senescent cells could be effective for the prevention and treatment of age-associated diseases including cancer. In this Review, we discuss our current understanding of the tissue-specific and context-specific processes that influence immune surveillance of senescent cells. We highlight the need for further research examining senescence across additional settings as well as the role of unexplored immune cell populations.
Ferroptosis is an iron-dependent form of regulated cell death driven by disrupted iron homeostasis and uncontrolled lipid peroxidation. Various metabolites and enzymes regulate cellular sensitivity to ferroptosis by affecting iron, lipid and redox metabolism. These pathways not only signal ferroptotic cell death but also affect the biology of T cells. The pathways include mechanisms by which iron metabolism regulates T cell activation via transferrin receptor 1-mTOR signalling, mechanisms by which lipid peroxidation drives vulnerability to ferroptosis in tumour-infiltrating CD8+ T cells, and mechanisms by which redox networks are balanced to maintain T cell survival. Here, we highlight the T cell subset-specific effects of ferroptosis-related pathways and ferroptosis susceptibility, and the implications for immunotherapy. We also discuss the emerging therapeutic strategies, including ferroptosis-resistant adoptive T cell therapy and ferroptosis-inducing approaches, that enhance the efficacy of immune checkpoint blockade for cancer treatment. Finally, we propose a framework for precision T cell-based immunotherapies, positioning ferroptosis as a tunable node linking T cell biology to clinical innovations.
Understanding human biology in health and disease has entered a new era, one defined not just by better tools but by a fundamental shift in how biological knowledge is generated.
A preprint by Delclaux et al. reports that dendritic cells recirculate tumour antigen to the draining lymph nodes to re-engage tumour-egressed T cells and sustain the antitumour response.
A preprint by Ngiow et al. shows that intermittent PD1 blockade incorporating a ‘drug holiday’ preserves the proliferative and differentiation capacity of progenitor exhausted T cells.
The lineage distinction between inflammatory, defence-oriented, monocyte-derived macrophages and resident macrophages dedicated to tissue maintenance calls into question the primordial function of macrophages and offers untapped therapeutic targets in these cells.
Interleukin-18 (IL-18) is a pleiotropic cytokine of the IL-1 family that has an important role in antitumour and antiviral immunity. Growing interest in its therapeutic potential has led researchers to explore strategies that harness IL-18 to modulate the tumour microenvironment. For example, engineered T cells are being armoured with IL-18 to enhance adoptive cell therapies and strengthen other immunotherapy approaches. As these strategies move towards clinical application, a key translational challenge is identifying the molecular mechanisms that influence treatment response and resistance, crucial for guiding trial design and patient selection across tumour types. This Review revisits the fundamental biology of IL-18, including its origins, cellular sources and regulatory networks, particularly those involving IL-18 binding protein (IL-18BP) and IL-37. We discuss how IL-18 promotes interferon-γ (IFNγ) production within the tumour microenvironment, supporting M1-like macrophage polarization, CD8+ cytotoxic T cell and CD4+ T helper 1 cell responses, natural killer cell activity and durable T cell memory. We also discuss preclinical models of IL-18 delivery, including dendritic cell platforms and cellular therapies, and highlight emerging strategies such as IL-18BP blockade and IL-18-secreting CAR T cells. Finally, we review results from early clinical studies and outline key challenges for translation, including the dual protumour and antitumour roles of IL-18.
A preprint by Lunger et al. reports macrophage engineering through constitutively active synthetic cytokine receptors to induce polarization states that are unobtainable with natural cytokine receptors.
Each antigen-specific T cell population represents only a small fraction of the total T cell repertoire, yet these populations play a disproportionately large role in immune responses to viruses and cancer and act as key effectors in autoimmune disease. Understanding their behaviour and phenotypes is therefore crucial for elucidating disease mechanisms. The rarity of these cells and the difficulty of isolating them meant that most prior studies examined bulk, unselected T cell populations. Such approaches capture substantial heterogeneity arising from diverse antigen targets, HLA alleles and potential bystander cells, yet have shaped much of our understanding of T cell responses and phenotypes. In this Review, we discuss how a combination of fundamental and emerging technologies now enables the detailed study of antigen-specific T cells. We highlight how insights linking epitope specificity, T cell receptor (TCR) usage and functional profiles across blood and tissues are transforming our understanding of T cell immunity. Furthermore, we emphasize that the widespread adoption of paired TCR sequencing is generating antigen-specific TCR datasets that can serve as durable reference libraries, enabling future studies and immune atlases to annotate and characterize antigen-specific T cell responses within broader datasets.
Since the first clinical approval in 2017, chimeric antigen receptor (CAR) T cell therapy has emerged as one of the most powerful modalities for redirecting the immune response against cancer. Building on decades of foundational discoveries in T cell biology and synthetic immunoengineering, CAR T cell therapy has transformed the treatment of B cell malignancies, resulting in durable remissions in patients with B cell leukaemias, lymphomas and multiple myeloma. Next-generation CAR designs are now expanding the reach of this approach into autoimmune disease and solid tumours. Innovations in gene editing, allogeneic manufacturing and in vivo delivery are improving the scalability, safety and accessibility of CAR T cell therapies, although challenges persist in overcoming antigen heterogeneity and tumour microenvironmental barriers and in promoting the long-term persistence of CAR T cells. In this Review, we summarize the key discoveries that laid the foundations for CAR T cell therapies and provide a broad overview of the current principles of CAR design, their clinical development and emerging strategies aimed at enhancing efficacy, broadening indications and achieving durable immune control across disease types.
Macrophages are essential components of the innate immune system and have crucial roles in host defence, tissue homeostasis and inflammation. Embryonic macrophages are specialized populations of macrophages that arise early during development and contribute to tissue organization, immune system development and homeostasis. These cells originate from yolk sac and fetal liver progenitors and colonize various tissues during embryogenesis, becoming long-lived tissue-resident macrophages. In the embryo, macrophages are involved in a wide range of developmental processes, including the clearance of apoptotic cells, regulation of organogenesis and establishment of tissue integrity. They are also pivotal in the early establishment of immune tolerance and in the development of the fetal haematopoietic and immune systems. Plenty of literature covers the role of yolk sac-derived macrophages in adult tissues, whereas less is known about their functions in the embryo itself. This Review highlights our emerging understanding of embryonic macrophages, their origin and their roles in organogenesis and development in mice and humans.
T cell engagers (TCEs) are antibody-based, bispecific or multi-specific constructs that can reprogramme T cells to eliminate target cells expressing a defined surface antigen. Originally developed for cancer therapy, TCEs are now being investigated for the treatment of autoimmune diseases, with promising initial results. The interest in using TCEs for autoimmune diseases is rapidly growing given their comparable potency with cellular therapies, combined with the advantages of biologics, including ease of manufacturing, off-the-shelf availability, better safety and more convenient delivery. Here we review the history of TCEs, focus on distinct aspects of the mechanism of action of TCEs and explain design principles. We also discuss key challenges for future TCE development in autoimmunity, including enhanced safety, high convenience and complete target cell elimination. Finally, we provide an overview of the preclinical and clinical development landscape and give an outlook on next-generation TCEs that are optimized to treat a wide variety of autoimmune diseases.
A preprint by Vick et al. reports a crucial role for vaginal NK cells in maintaining epithelial integrity during infection.
In this Viewpoint, eight experts from the field of T cell exhaustion discuss current understanding of the self-renewing population of PD1+TCF1+TOX+ precursor and/or progenitor exhausted CD8+ T cells and controversies related to their development and function.
A preprint by Serganova, Colombo et al. shows that tumour glycolytic capacity drives vascular abnormalities that influence the response to immunotherapy.
Twentieth-century immunology was shaped by questions of recognition, diversity, response and tolerance. The next era may be defined by a different class of questions: how immune activity is embedded in organ physiology, inter-organ homeostasis and human biology.
