Pub Date : 2025-10-09DOI: 10.1038/s41577-025-01223-9
Jeremy G. Baldwin, Christoph Heuser-Loy, Luca Gattinoni
Organelles are the internal batteries, gears, actuators, 3D printers and transmitters that drive cell function. Their composition and activity vary between cell types depending on functional demands. In T cells, which are key mediators of immunosurveillance and tumour eradication, organelles are relatively few and function at basal levels when cells are at rest. However, upon activation, they increase in number and size and undergo extensive remodelling to support rapid proliferation, effector differentiation and adaptation to diverse microenvironments, including the tumour microenvironment, thereby enabling efficient clearance of target cells. In this Review, we provide an overview of recent advances in our understanding of how various organelles contribute to T cell-mediated antitumour immunity. We also discuss emerging strategies to modulate organelle functions — from organelle-targeted therapies and their use as cargo delivery systems to the transfer or transplantation of native or synthetic organelles — that have the potential to enhance cancer immunotherapies involving immune-checkpoint blockade or the adoptive transfer of T cells. 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.
{"title":"Targeting organelle function in T cells for cancer immunotherapy","authors":"Jeremy G. Baldwin, Christoph Heuser-Loy, Luca Gattinoni","doi":"10.1038/s41577-025-01223-9","DOIUrl":"10.1038/s41577-025-01223-9","url":null,"abstract":"Organelles are the internal batteries, gears, actuators, 3D printers and transmitters that drive cell function. Their composition and activity vary between cell types depending on functional demands. In T cells, which are key mediators of immunosurveillance and tumour eradication, organelles are relatively few and function at basal levels when cells are at rest. However, upon activation, they increase in number and size and undergo extensive remodelling to support rapid proliferation, effector differentiation and adaptation to diverse microenvironments, including the tumour microenvironment, thereby enabling efficient clearance of target cells. In this Review, we provide an overview of recent advances in our understanding of how various organelles contribute to T cell-mediated antitumour immunity. We also discuss emerging strategies to modulate organelle functions — from organelle-targeted therapies and their use as cargo delivery systems to the transfer or transplantation of native or synthetic organelles — that have the potential to enhance cancer immunotherapies involving immune-checkpoint blockade or the adoptive transfer of T cells. 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.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":"26 3","pages":"170-188"},"PeriodicalIF":60.9,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145254762","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 : 2025-10-08DOI: 10.1038/s41577-025-01233-7
Yvonne Bordon
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.
{"title":"Autoimmune T cells identified in ALS","authors":"Yvonne Bordon","doi":"10.1038/s41577-025-01233-7","DOIUrl":"10.1038/s41577-025-01233-7","url":null,"abstract":"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.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":"25 11","pages":"781-781"},"PeriodicalIF":60.9,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246599","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 : 2025-10-07DOI: 10.1038/s41577-025-01234-6
Alexandra Flemming
Depending on context and concentration, the polyamine cadaverine can promote pro- or anti-inflammatory macrophage polarizations.
根据不同的环境和浓度，多胺尸胺可以促进或抗炎巨噬细胞极化。
{"title":"Enterobacteriaceae-derived cadaverine manipulates gut macrophage metabolism","authors":"Alexandra Flemming","doi":"10.1038/s41577-025-01234-6","DOIUrl":"10.1038/s41577-025-01234-6","url":null,"abstract":"Depending on context and concentration, the polyamine cadaverine can promote pro- or anti-inflammatory macrophage polarizations.","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":"145241099","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 : 2025-10-07DOI: 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}
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