Nat Rev Immunol
· 2026 Jun · PMID 41577820
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JAK inhibitors target a large group of cytokines that signal through the JAK-STAT pathway and are typically used clinically as immunosuppressive agents. However, recent work has demonstrated the paradoxical ability of JA...JAK inhibitors target a large group of cytokines that signal through the JAK-STAT pathway and are typically used clinically as immunosuppressive agents. However, recent work has demonstrated the paradoxical ability of JAK inhibitors to enhance antitumour and antiviral immune responses and established their synergy with immune checkpoint inhibitors in early-stage clinical trials. In this Perspective, we consider why JAK inhibitors, which are typically used as immunosuppressive drugs, can have immune-enhancing effects, exploring the potential mechanistic basis and the opportunities to harness this effect to improve cancer immunotherapy.
In the context of adaptive immunity, T cells are activated by professional antigen-presenting cells (APCs) in a process that begins with peptide-MHC complexes on the APC being recognized by T cell receptor and CD3 co-rec...In the context of adaptive immunity, T cells are activated by professional antigen-presenting cells (APCs) in a process that begins with peptide-MHC complexes on the APC being recognized by T cell receptor and CD3 co-receptor complexes on the T cell. This triggers a reorganization of T cell morphology, formation of an immune synapse, and the delivery of signals that ultimately culminate in nuclear activation. The interaction between T cells and APCs, such as dendritic cells (DCs), was originally viewed as a unidirectional information highway in which the APC instructs the T cell. It is now clear that bidirectional crosstalk occurs at the immune synapse and that T cells also shape APC functions. The concept of 'DC licensing' originally suggested an instructive role for T cells in modifying DC functions. More recent studies have provided important insight into the changes that occur in DCs during antigen-driven contacts with T cells at the immune synapse. In this Review, we discuss our current understanding of the bidirectional T cell-DC crosstalk that occurs at the IS and its relevance for immune responses and immunotherapies.
Infection triggers one of the most dramatic systemic responses in the body, and the coordinated activation and function of immune cells requires a dynamic regulation of transcriptomes and proteomes. This is achieved by R...Infection triggers one of the most dramatic systemic responses in the body, and the coordinated activation and function of immune cells requires a dynamic regulation of transcriptomes and proteomes. This is achieved by RNA-binding proteins, which, together with RNA, form ribonucleoproteins. These proteins expand the information content of the genome and determine the lifespan, localization and function of RNA. Moreover, they control when, where and how much protein is produced. They can also mediate cell-autonomous immunity to foreign RNA and to misfolded self-RNAs and ensure the fidelity of the transcriptome by acting as RNA modifiers and chaperones to prevent RNA misfolding. These activities are integrated with gene expression programmes that are induced by the pathogen-sensing mechanisms of immune cells, which together activate, and later resolve, immune responses. Here, we review the activities of RNA-binding proteins in immune cells and discuss how perturbations of their function can result in immunodeficiency, autoimmunity and chronic inflammation.
Alterations in key metabolic pathways are required for tumour development and the adaptation of tumour cells to intrinsic or extrinsic stresses, as well as for the regulation of immune cell fate and immune responses in t...Alterations in key metabolic pathways are required for tumour development and the adaptation of tumour cells to intrinsic or extrinsic stresses, as well as for the regulation of immune cell fate and immune responses in the tumour microenvironment. In particular, the dysregulation or alteration of certain metabolites produced by tumour cells has been shown to be important in creating the immunosuppressive tumour microenvironment. Recent studies have broadened our understanding of the interactions between metabolites and antitumour immunity. Here we highlight how, beyond their metabolic role, metabolites can function as signalling molecules to modulate the behaviours of immune cells and tumour cells. We also discuss potential therapeutic strategies targeting specific metabolites and future research directions in metabolite sensing.
Within the IL-12 superfamily of heterodimeric cytokines, IL-12 and IL-23, which share a subunit, are among the most pro-inflammatory members. Both are primarily produced by phagocytes and have key roles in activating and...Within the IL-12 superfamily of heterodimeric cytokines, IL-12 and IL-23, which share a subunit, are among the most pro-inflammatory members. Both are primarily produced by phagocytes and have key roles in activating and regulating T lymphocytes, natural killer cells and innate lymphoid cells. IL-12 predominantly promotes type 1 immune responses, whereas IL-23 is closely associated with type 3 immunity. Their receptors are also heterodimeric and, upon engagement, they trigger 'cytokine polarization' (the imprinting of functional identities on immune cells by activating lineage-defining transcription factors), which contributes to inflammation and immunopathology. IL-12 has a key role in various inflammatory conditions and is a potent driver of antitumour immunity, and IL-12 delivery is being explored in several clinical trials in cancer. By contrast, IL-23 is essential for maintaining barrier tissue integrity, yet its dysregulation is a central driver of autoimmune diseases such as psoriasis. Beyond their well-established pro-inflammatory roles, studies of both cytokines have also yielded paradoxical findings. Emerging evidence suggests that both IL-12 and IL-23 can also attenuate immune responses. In this Review, we explore the discovery of IL-12 and IL-23, their canonical pro-inflammatory functions, and recent insights into their immunoregulatory roles in inflammation, cancer and autoimmunity.
The extracellular matrix (ECM) constitutes the bulk between cells, establishes barriers that separate tissue compartments, and defines the form and pliability of organs. The ECM is an integral part of the cellular microe...The extracellular matrix (ECM) constitutes the bulk between cells, establishes barriers that separate tissue compartments, and defines the form and pliability of organs. The ECM is an integral part of the cellular microenvironment, conveying a multitude of biochemical (and mechanical) signals to associated cells, for example, by binding cytokines and chemotactic factors. All cells are in contact with the ECM, including immune cells in lymphoid organs and when they extravasate from blood vessels, as well as tissue-resident myeloid cells in close contact with the ECM of blood vessels. The past decade has seen technical advances in proteomics and transcriptomics that have provided large volumes of data on the diversity of the ECM and of the immune system. It is important to assess this rapidly growing body of data together with knowledge of the in vivo situation, particularly from more than a decade of intravital imaging studies. This Review summarizes both biochemical and imaging data that are relevant to leukocyte extravasation across the ECM - in particular, the basement membrane - to enter sites of inflammation, as well as the changes to the ECM that are associated with chronic inflammation, including tumour sites. It also discusses how this information may be exploited for the development of novel immunotherapies.
The immune system has evolved intricate and sophisticated mechanisms to recognize and eliminate tumours. Among these, T helper 17 (T17) cells seem to have a complex role in tumour immunity. Substantial evidence indicates...The immune system has evolved intricate and sophisticated mechanisms to recognize and eliminate tumours. Among these, T helper 17 (T17) cells seem to have a complex role in tumour immunity. Substantial evidence indicates that T17 cells can impair the ability of immune cells to kill tumours, but growing research suggests that T17 cells may also be crucial for facilitating effective antitumour immune responses. This apparent paradox is likely rooted, at least in part, in the remarkable plasticity of T17 cells, which can adopt a range of effector functions depending on the environmental cues present in distinct tissue niches. Understanding the spectrum of functional adaptations that T17 cells can undergo is especially important in cancer, where tumours exhibit substantial tissue heterogeneity. Here, we examine the context-dependent roles of T17 cells in cancer, with a focus on the environmental signals and regulatory networks that may shape their phenotypes during cancer development and progression. Finally, we discuss how these insights could inform strategies to manipulate T17 cells for the development of next-generation cancer immunotherapies.
Ubiquitination, the covalent attachment of ubiquitin to proteins and other cellular substrates, is a dynamic post-translational modification that enables cells to rapidly respond to internal and external threats. Beyond...Ubiquitination, the covalent attachment of ubiquitin to proteins and other cellular substrates, is a dynamic post-translational modification that enables cells to rapidly respond to internal and external threats. Beyond its canonical role in targeting proteins for proteasomal degradation, ubiquitination orchestrates the assembly of signalling complexes that regulate innate and adaptive immune responses, modulates inflammatory pathways and directs selective autophagy to eliminate intracellular pathogens through lysosomal degradation. To persist and replicate within the host, viruses, bacteria and parasites have evolved diverse mechanisms to evade, manipulate or exploit the host's ubiquitin and autophagy machinery. Some pathogens subvert these systems to dampen immune surveillance, whereas others co-opt them to facilitate replication or dissemination. In this Review, we examine how ubiquitin and autophagy shape host-pathogen interactions, uncover common and pathogen-specific strategies of immune evasion, and discuss emerging therapeutic approaches that aim to leverage these interconnected pathways to enhance antimicrobial immunity.
Vitiligo is an autoimmune disease of melanocyte destruction, which manifests as progressive, patchy loss of pigmentation in the skin. As one of most common autoimmune diseases, vitiligo inflicts a significant psychosocia...Vitiligo is an autoimmune disease of melanocyte destruction, which manifests as progressive, patchy loss of pigmentation in the skin. As one of most common autoimmune diseases, vitiligo inflicts a significant psychosocial burden. Research over the past two decades has revealed the underlying immune mechanisms of vitiligo, with key studies combining detailed analyses of patient tissue samples with mechanistic experiments in mouse models. Vitiligo has emerged as a prototypical CD8 T cell-mediated autoimmune disease, with cooperation between innate immune cells, dendritic cells, T cells, keratinocytes and fibroblasts driving autoimmune pathology against the uniquely susceptible melanocyte target. The study of vitiligo has also revealed aspects of CD8 T cell memory and resident memory against self-antigens. This work has drawn from, and contributed to, the study of melanoma immunology. Whereas drugs used for other autoimmune conditions have been largely ineffective in treating vitiligo, a growing base of knowledge recently led to the first successful FDA-approved immune-modulating drugs for vitiligo. This review focuses on the immunology of vitiligo: the mechanisms that drive melanocyte destruction, the biology of aberrant T cell responses against melanocytes and therapeutic means for counteracting this autoimmune condition.