Pub Date : 2025-10-07DOI: 10.1038/s41577-025-01236-4
Alexandra Flemming
A proteotoxic stress response specific to exhausted T cells represents a target for cancer immunotherapy.
一种针对衰竭T细胞的蛋白毒性应激反应是癌症免疫治疗的靶标。
{"title":"Proteotoxic shock is a mechanistic driver of T cell exhaustion","authors":"Alexandra Flemming","doi":"10.1038/s41577-025-01236-4","DOIUrl":"10.1038/s41577-025-01236-4","url":null,"abstract":"A proteotoxic stress response specific to exhausted T cells represents a target for cancer immunotherapy.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":"25 11","pages":"781-781"},"PeriodicalIF":60.9,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-06DOI: 10.1038/s41577-025-01227-5
Jasia Mahdi, Vrunda Trivedi, Michelle Monje
The nervous and immune systems are intricately linked to one another through bi-directional crosstalk. Given the limited therapeutic options for aggressive and refractory central nervous system (CNS) tumours, immunotherapies are increasingly being explored as potential treatments for these malignancies. In this Review, we provide an overview of the nervous system–immune system connections that provide the basis for the use of immunotherapy to treat CNS tumours. We then summarize the outcomes from preclinical and clinical studies that have used immunotherapies, including chimeric antigen receptor T cell therapy, oncolytic viruses, cancer vaccines and immune-checkpoint inhibitors, for the treatment of primary CNS cancers such as high-grade gliomas, refractory embryonal brain tumours and primary CNS lymphomas. Finally, we review the neurological symptoms and syndromes that can arise with these immunotherapeutic approaches. 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.
{"title":"The promise of immunotherapy for central nervous system tumours","authors":"Jasia Mahdi, Vrunda Trivedi, Michelle Monje","doi":"10.1038/s41577-025-01227-5","DOIUrl":"10.1038/s41577-025-01227-5","url":null,"abstract":"The nervous and immune systems are intricately linked to one another through bi-directional crosstalk. Given the limited therapeutic options for aggressive and refractory central nervous system (CNS) tumours, immunotherapies are increasingly being explored as potential treatments for these malignancies. In this Review, we provide an overview of the nervous system–immune system connections that provide the basis for the use of immunotherapy to treat CNS tumours. We then summarize the outcomes from preclinical and clinical studies that have used immunotherapies, including chimeric antigen receptor T cell therapy, oncolytic viruses, cancer vaccines and immune-checkpoint inhibitors, for the treatment of primary CNS cancers such as high-grade gliomas, refractory embryonal brain tumours and primary CNS lymphomas. Finally, we review the neurological symptoms and syndromes that can arise with these immunotherapeutic approaches. 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.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":"26 3","pages":"213-229"},"PeriodicalIF":60.9,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145235978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-03DOI: 10.1038/s41577-025-01232-8
Kirsty Minton
A study in Science Immunology reports that regulatory T cells in the skin modulate neuronal tone directly through their production of the opioid enkephalin.
《科学免疫学》上的一项研究报告称，皮肤中的调节性T细胞通过产生阿片样物质脑啡肽直接调节神经元张力。
{"title":"Skin Treg cells set the tone for neuronal activation","authors":"Kirsty Minton","doi":"10.1038/s41577-025-01232-8","DOIUrl":"10.1038/s41577-025-01232-8","url":null,"abstract":"A study in Science Immunology reports that regulatory T cells in the skin modulate neuronal tone directly through their production of the opioid enkephalin.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":"25 11","pages":"780-780"},"PeriodicalIF":60.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01DOI: 10.1038/s41577-025-01221-x
Qinli Sun, Chen Dong
T cell exhaustion is an adaptive and distinct cell fate that emerges in response to persistent antigen stimulation, primarily in chronic infections and cancer. It is characterized by a progressive loss of effector functions and sustained expression of multiple inhibitory receptors. Progression to T cell exhaustion is driven by persistent antigen stimulation through the T cell receptor and is modulated by signals from co-stimulatory and inhibitory molecules as well as by microenvironmental factors such as cytokines, metabolites and neuronal factors. These extrinsic cellular factors reshape the T cell transcriptome, epigenome and metabolism towards a state of exhaustion through critical intrinsic cell regulators. In this Review, we summarize our current understanding of the regulators involved in T cell exhaustion, highlighting their roles in directing the fates and functionalities of distinct exhausted T cell subsets and how they may be harnessed for the development of improved immunotherapies against cancer and chronic infections. 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.
{"title":"Regulators of CD8+ T cell exhaustion","authors":"Qinli Sun, Chen Dong","doi":"10.1038/s41577-025-01221-x","DOIUrl":"10.1038/s41577-025-01221-x","url":null,"abstract":"T cell exhaustion is an adaptive and distinct cell fate that emerges in response to persistent antigen stimulation, primarily in chronic infections and cancer. It is characterized by a progressive loss of effector functions and sustained expression of multiple inhibitory receptors. Progression to T cell exhaustion is driven by persistent antigen stimulation through the T cell receptor and is modulated by signals from co-stimulatory and inhibitory molecules as well as by microenvironmental factors such as cytokines, metabolites and neuronal factors. These extrinsic cellular factors reshape the T cell transcriptome, epigenome and metabolism towards a state of exhaustion through critical intrinsic cell regulators. In this Review, we summarize our current understanding of the regulators involved in T cell exhaustion, highlighting their roles in directing the fates and functionalities of distinct exhausted T cell subsets and how they may be harnessed for the development of improved immunotherapies against cancer and chronic infections. 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.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":"26 2","pages":"129-151"},"PeriodicalIF":60.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-22DOI: 10.1038/s41577-025-01222-w
Francesca Fallarino, Christian U. Blank
Immunotherapy has become a fourth pillar of cancer therapy, alongside surgery, radiotherapy and chemotherapy. Cancer immunotherapy seems to be most effective in the context of low but not negligible tumour burden, thus in the neoadjuvant setting before curative intent surgery. Indeed, in the case of macroscopic stage III melanoma, a decade of clinical and translational research has led to conclusive evidence that neoadjuvant immunotherapy should be the clinical standard of care, although its adoption in different regions of the world is still ongoing. In this Perspective, we discuss the lessons learnt from neoadjuvant immunotherapy trials in melanoma and where the field is heading next. In the coming years, we believe that biomarker-driven personalization of the therapy, a deeper understanding of the role of immune education, and the ability to uncouple toxicity from efficacy will make neoadjuvant cancer immunotherapy safer and more effective, not only for melanoma but also for other types of cancer. 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.
{"title":"Lessons from neoadjuvant immunotherapy in melanoma: understanding antitumour immunity and tumour escape","authors":"Francesca Fallarino, Christian U. Blank","doi":"10.1038/s41577-025-01222-w","DOIUrl":"10.1038/s41577-025-01222-w","url":null,"abstract":"Immunotherapy has become a fourth pillar of cancer therapy, alongside surgery, radiotherapy and chemotherapy. Cancer immunotherapy seems to be most effective in the context of low but not negligible tumour burden, thus in the neoadjuvant setting before curative intent surgery. Indeed, in the case of macroscopic stage III melanoma, a decade of clinical and translational research has led to conclusive evidence that neoadjuvant immunotherapy should be the clinical standard of care, although its adoption in different regions of the world is still ongoing. In this Perspective, we discuss the lessons learnt from neoadjuvant immunotherapy trials in melanoma and where the field is heading next. In the coming years, we believe that biomarker-driven personalization of the therapy, a deeper understanding of the role of immune education, and the ability to uncouple toxicity from efficacy will make neoadjuvant cancer immunotherapy safer and more effective, not only for melanoma but also for other types of cancer. 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.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":"26 2","pages":"152-162"},"PeriodicalIF":60.9,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-22DOI: 10.1038/s41577-025-01228-4
Rayne H. Rouce
Unique barriers to treatment with chimeric antigen receptor (CAR)-T cells prevent many patients with cancer from benefitting from these potentially lifesaving therapies. Here I explore the complex matrix of logistical red tape and financial obstacles that block the road to broader clinical adoption of CAR-T cell therapy, both in the USA and globally, and propose new routes to improve timely and equitable access to treatment. 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.
{"title":"Clearing the hurdles for CAR-T cell treatment","authors":"Rayne H. Rouce","doi":"10.1038/s41577-025-01228-4","DOIUrl":"10.1038/s41577-025-01228-4","url":null,"abstract":"Unique barriers to treatment with chimeric antigen receptor (CAR)-T cells prevent many patients with cancer from benefitting from these potentially lifesaving therapies. Here I explore the complex matrix of logistical red tape and financial obstacles that block the road to broader clinical adoption of CAR-T cell therapy, both in the USA and globally, and propose new routes to improve timely and equitable access to treatment. 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.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":"25 11","pages":"777-779"},"PeriodicalIF":60.9,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-12DOI: 10.1038/s41577-025-01215-9
Seung Bum Park, Paul Zimmer-Harwood, T. Jake Liang
Hepatitis C virus (HCV) remains a serious global health burden that affects nearly 50 million people worldwide. Despite the availability of highly effective direct-acting antiviral drugs, the lack of an effective HCV vaccine hinders control and elimination worldwide, wherein new infections and overall prevalence remain high. HCV vaccine development faces challenges including high genetic diversity of the virus, unclear correlates of protective immunity, and lack of robust in vivo models for vaccine testing. Despite these obstacles, the landscape of HCV vaccine development is rapidly evolving. Innovative strategies, including subunit, virus-like particle, viral vector, DNA and RNA vaccines, show promising results, and controlled human infection models offer a unique, albeit ethically complex, opportunity to accelerate vaccine development. Collaborative efforts among academia, industry, governmental agencies and regulatory bodies are crucial for optimizing vaccine strategies, overcoming current challenges and effecting advances towards global HCV elimination through vaccination. 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.
{"title":"Targets of protective immunity and opportunities in hepatitis C virus vaccine development","authors":"Seung Bum Park, Paul Zimmer-Harwood, T. Jake Liang","doi":"10.1038/s41577-025-01215-9","DOIUrl":"10.1038/s41577-025-01215-9","url":null,"abstract":"Hepatitis C virus (HCV) remains a serious global health burden that affects nearly 50 million people worldwide. Despite the availability of highly effective direct-acting antiviral drugs, the lack of an effective HCV vaccine hinders control and elimination worldwide, wherein new infections and overall prevalence remain high. HCV vaccine development faces challenges including high genetic diversity of the virus, unclear correlates of protective immunity, and lack of robust in vivo models for vaccine testing. Despite these obstacles, the landscape of HCV vaccine development is rapidly evolving. Innovative strategies, including subunit, virus-like particle, viral vector, DNA and RNA vaccines, show promising results, and controlled human infection models offer a unique, albeit ethically complex, opportunity to accelerate vaccine development. Collaborative efforts among academia, industry, governmental agencies and regulatory bodies are crucial for optimizing vaccine strategies, overcoming current challenges and effecting advances towards global HCV elimination through vaccination. 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.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":"26 2","pages":"112-128"},"PeriodicalIF":60.9,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145035166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-10DOI: 10.1038/s41577-025-01214-w
Loïc Dupré, Irinka Castanon, Kaan Boztug
Actin cytoskeleton remodelling drives the migration of immune cells and their engagement in dynamic cell–cell contacts. The importance of actin cytoskeleton dynamics in immune cell function is highlighted by the discovery of inborn errors of immunity (IEIs) that are caused by defects in individual actin-regulatory proteins, resulting in immune-related actinopathies. In addition to susceptibility to infection, these often present with a vast array of autoimmune and autoinflammatory manifestations. Here, we review the role of actin subnetworks in the activation and function of lymphoid and myeloid cells. We focus on the mechanisms by which actin defects result in aberrant lymphocyte function, including dysregulation of T cell- and B cell-mediated tolerance and biased cytokine production, which can result in autoimmunity. We also highlight the relationship between actin defects and inflammasome activation and other pathomechanisms in myeloid cells as the underlying cause of autoinflammation. Finally, we discuss future avenues for research and therapeutic intervention based on a molecular understanding of immune-related actinopathies. 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.
{"title":"Immune-related actinopathies at the cross-road of immunodeficiency, autoimmunity and autoinflammation","authors":"Loïc Dupré, Irinka Castanon, Kaan Boztug","doi":"10.1038/s41577-025-01214-w","DOIUrl":"10.1038/s41577-025-01214-w","url":null,"abstract":"Actin cytoskeleton remodelling drives the migration of immune cells and their engagement in dynamic cell–cell contacts. The importance of actin cytoskeleton dynamics in immune cell function is highlighted by the discovery of inborn errors of immunity (IEIs) that are caused by defects in individual actin-regulatory proteins, resulting in immune-related actinopathies. In addition to susceptibility to infection, these often present with a vast array of autoimmune and autoinflammatory manifestations. Here, we review the role of actin subnetworks in the activation and function of lymphoid and myeloid cells. We focus on the mechanisms by which actin defects result in aberrant lymphocyte function, including dysregulation of T cell- and B cell-mediated tolerance and biased cytokine production, which can result in autoimmunity. We also highlight the relationship between actin defects and inflammasome activation and other pathomechanisms in myeloid cells as the underlying cause of autoinflammation. Finally, we discuss future avenues for research and therapeutic intervention based on a molecular understanding of immune-related actinopathies. 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.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":"26 2","pages":"89-111"},"PeriodicalIF":60.9,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-08DOI: 10.1038/s41577-025-01219-5
Thomas Riffelmacher, Mitchell Kronenberg
Immunometabolism, the intersection of cellular metabolism and immune function, has revolutionized our understanding of T cell biology. Changes in cellular metabolism help guide the development of thymocytes and the transition of T cells from naive to effector, memory and tissue-resident states. Innate-like T cells are a unique group of T cells with special characteristics. They respond rapidly, reside mainly in tissues and express T cell receptors with limited diversity that recognize non-peptide antigens. This group includes invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells and some populations of γδ T cells. Different subsets of innate-like T cells rely on specific metabolic pathways that influence their differentiation and function and distinguish them from conventional CD4+ and CD8+ T cells. Although there are differences between innate-like T cell types, they share metabolic and functional features. In this Review, we highlight recent research in this emerging field. Understanding how metabolic programmes differ between innate-like T cells and other T cells may open opportunities for tailoring innate-like T cell responses and adoptive T cell therapies for use in cancer, metabolic and autoimmune diseases. 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.
{"title":"Metabolic control of innate-like T cells","authors":"Thomas Riffelmacher, Mitchell Kronenberg","doi":"10.1038/s41577-025-01219-5","DOIUrl":"10.1038/s41577-025-01219-5","url":null,"abstract":"Immunometabolism, the intersection of cellular metabolism and immune function, has revolutionized our understanding of T cell biology. Changes in cellular metabolism help guide the development of thymocytes and the transition of T cells from naive to effector, memory and tissue-resident states. Innate-like T cells are a unique group of T cells with special characteristics. They respond rapidly, reside mainly in tissues and express T cell receptors with limited diversity that recognize non-peptide antigens. This group includes invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells and some populations of γδ T cells. Different subsets of innate-like T cells rely on specific metabolic pathways that influence their differentiation and function and distinguish them from conventional CD4+ and CD8+ T cells. Although there are differences between innate-like T cell types, they share metabolic and functional features. In this Review, we highlight recent research in this emerging field. Understanding how metabolic programmes differ between innate-like T cells and other T cells may open opportunities for tailoring innate-like T cell responses and adoptive T cell therapies for use in cancer, metabolic and autoimmune diseases. 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.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":"26 1","pages":"67-82"},"PeriodicalIF":60.9,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145017916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-03DOI: 10.1038/s41577-025-01218-6
Klaus Früh, Persephone Borrow, Geraldine M. Gillespie, Andrew J. McMichael, Louis J. Picker
MHC-E is a highly conserved, non-polymorphic MHC protein that engages inhibitory and activating receptors on natural killer (NK) cells and T cells and can also present antigens to T cell receptors. NK cell responses driven by activating receptor interactions with MHC-E are implicated in controlling chronic viral infections and cancer. Immunotherapeutic targeting of interactions between MHC-E and inhibitory receptors to increase the activation of NK cells and T cells shows promise in improving antitumour immune responses. Furthermore, MHC-E-restricted CD8+ T cells elicited by cytomegalovirus-based vaccines might, for certain infections and cancers, be more effective than CD8+ T cells restricted by classical MHC class I or class II molecules. The ability of MHC-E to regulate or mediate both innate and adaptive immune responses independently of the MHC haplotype of an individual raises the possibility of new, universally effective vaccines and immunotherapies for infectious disease and cancer. Although the therapeutic exploitation of MHC-E is still in its infancy, recent advances in the understanding of MHC-E biology show enormous potential, as described in this Review. 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.
{"title":"Targeting MHC-E as a new strategy for vaccines and immunotherapeutics","authors":"Klaus Früh, Persephone Borrow, Geraldine M. Gillespie, Andrew J. McMichael, Louis J. Picker","doi":"10.1038/s41577-025-01218-6","DOIUrl":"10.1038/s41577-025-01218-6","url":null,"abstract":"MHC-E is a highly conserved, non-polymorphic MHC protein that engages inhibitory and activating receptors on natural killer (NK) cells and T cells and can also present antigens to T cell receptors. NK cell responses driven by activating receptor interactions with MHC-E are implicated in controlling chronic viral infections and cancer. Immunotherapeutic targeting of interactions between MHC-E and inhibitory receptors to increase the activation of NK cells and T cells shows promise in improving antitumour immune responses. Furthermore, MHC-E-restricted CD8+ T cells elicited by cytomegalovirus-based vaccines might, for certain infections and cancers, be more effective than CD8+ T cells restricted by classical MHC class I or class II molecules. The ability of MHC-E to regulate or mediate both innate and adaptive immune responses independently of the MHC haplotype of an individual raises the possibility of new, universally effective vaccines and immunotherapies for infectious disease and cancer. Although the therapeutic exploitation of MHC-E is still in its infancy, recent advances in the understanding of MHC-E biology show enormous potential, as described in this Review. 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.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":"26 1","pages":"52-66"},"PeriodicalIF":60.9,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144930867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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