Pub Date : 2025-10-16DOI: 10.1038/s41577-025-01226-6
Daniel A. Winer, Huixun Du, JangKeun Kim, Veronica Chang, Marissa Burke, Shawn Winer, Sylvain V. Costes, Jean-Pol Frippiat, Clarence Sams, Amber M. Paul, Honglu Wu, Oliver Ullrich, Sarah Baatout, Afshin Beheshti, Christopher E. Mason, Alexander Choukér, Brian E. Crucian
As humans embark on longer and deeper missions into space, it is crucial to understand how spaceflight impacts the immune system. Decades of discoveries, bolstered by recent multiomic analyses, have identified key immune processes that are affected by the spaceflight environment. These findings form the foundations of the emerging field of ‘astroimmunology’. Spaceflight stressors — such as microgravity and galactic cosmic radiation — and other mission-associated variables, including psychological stress and abnormal circadian rhythms, can disrupt or adversely affect immune cell biology. In addition, spaceflight alters host–microbiome interactions, which can increase susceptibility to opportunistic pathogens and viral reactivation. Although ground-based analogues for human spaceflight have provided insights into these stressors individually, their combined effects during spaceflight remain less understood. This Review explores our current knowledge of the effects of spaceflight stressors on the immune system and the clinical implications for human space exploration. It also highlights current and developing countermeasures, including machine-learning approaches, advanced monitoring technologies and standardized biobanking, that can facilitate research into the impact of spaceflight on the immune system. Looking ahead, progressing from low Earth orbit missions to long-term missions to the Moon, Mars and beyond will introduce new challenges, including increased radiation, variable gravity and regolith exposure. We discuss these prospective challenges and outline potential preventive and mitigative strategies for sustaining immune health to enable safe and effective space exploration and habitation of distant worlds. As more spaceflight missions plan to take humans back to the moon — and beyond — a key goal is to understand how spaceflight affects the immune system. In this Review, researchers from academia and international space agencies discuss the emergence of the field of ‘astroimmunology’. They outline the main immunological challenges we must overcome to facilitate safe space exploration by humans.
{"title":"Astroimmunology: the effects of spaceflight and its associated stressors on the immune system","authors":"Daniel A. Winer, Huixun Du, JangKeun Kim, Veronica Chang, Marissa Burke, Shawn Winer, Sylvain V. Costes, Jean-Pol Frippiat, Clarence Sams, Amber M. Paul, Honglu Wu, Oliver Ullrich, Sarah Baatout, Afshin Beheshti, Christopher E. Mason, Alexander Choukér, Brian E. Crucian","doi":"10.1038/s41577-025-01226-6","DOIUrl":"10.1038/s41577-025-01226-6","url":null,"abstract":"As humans embark on longer and deeper missions into space, it is crucial to understand how spaceflight impacts the immune system. Decades of discoveries, bolstered by recent multiomic analyses, have identified key immune processes that are affected by the spaceflight environment. These findings form the foundations of the emerging field of ‘astroimmunology’. Spaceflight stressors — such as microgravity and galactic cosmic radiation — and other mission-associated variables, including psychological stress and abnormal circadian rhythms, can disrupt or adversely affect immune cell biology. In addition, spaceflight alters host–microbiome interactions, which can increase susceptibility to opportunistic pathogens and viral reactivation. Although ground-based analogues for human spaceflight have provided insights into these stressors individually, their combined effects during spaceflight remain less understood. This Review explores our current knowledge of the effects of spaceflight stressors on the immune system and the clinical implications for human space exploration. It also highlights current and developing countermeasures, including machine-learning approaches, advanced monitoring technologies and standardized biobanking, that can facilitate research into the impact of spaceflight on the immune system. Looking ahead, progressing from low Earth orbit missions to long-term missions to the Moon, Mars and beyond will introduce new challenges, including increased radiation, variable gravity and regolith exposure. We discuss these prospective challenges and outline potential preventive and mitigative strategies for sustaining immune health to enable safe and effective space exploration and habitation of distant worlds. As more spaceflight missions plan to take humans back to the moon — and beyond — a key goal is to understand how spaceflight affects the immune system. In this Review, researchers from academia and international space agencies discuss the emergence of the field of ‘astroimmunology’. They outline the main immunological challenges we must overcome to facilitate safe space exploration by humans.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":"26 3","pages":"189-212"},"PeriodicalIF":60.9,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305720","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 : 2025-10-14DOI: 10.1038/s41577-025-01229-3
Zachary L. Lamplugh, Nils Wellhausen, Carl H. June, Yi Fan
Chimeric antigen receptor (CAR) T cell therapy holds significant promise for the treatment of cancer; however, its efficacy in solid tumours is substantially hindered by the immunosuppressive tumour microenvironment (TME). Solid tumours can resist immunotherapy by impairing T cell trafficking, function and persistence. One of the initial obstacles that CAR T cells encounter is the abnormal tumour vasculature, which restricts efficient T cell infiltration, further compounded by a dense extracellular matrix. CAR T cells that do infiltrate the tumours are outnumbered by immunosuppressive cells such as regulatory T cells, myeloid-derived suppressor cells and tumour-associated macrophages. Additionally, tumour cells can contribute to CAR T cell resistance by upregulating immune checkpoint molecules, such as PDL1 and CTLA4, and engage in metabolic competition. In this Review, we discuss how cellular and non-cellular components of the TME impair CAR T cell therapy and consider potential strategies to improve CAR T cell therapies for solid tumours, either by reprogramming the TME or by engineering CAR T cells to resist the immunosuppressive effects of the TME. The tumour microenvironment (TME) poses a significant obstacle to the success of chimeric antigen receptor (CAR) T cell immunotherapy in solid tumours. Here, the authors detail how both cellular and non-cellular components of the TME contribute to tumour resistance against CAR T cell therapy, and explore emerging strategies aimed at overcoming these barriers in order to enhance the efficacy of CAR T cell therapy.
{"title":"Microenvironmental regulation of solid tumour resistance to CAR T cell therapy","authors":"Zachary L. Lamplugh, Nils Wellhausen, Carl H. June, Yi Fan","doi":"10.1038/s41577-025-01229-3","DOIUrl":"10.1038/s41577-025-01229-3","url":null,"abstract":"Chimeric antigen receptor (CAR) T cell therapy holds significant promise for the treatment of cancer; however, its efficacy in solid tumours is substantially hindered by the immunosuppressive tumour microenvironment (TME). Solid tumours can resist immunotherapy by impairing T cell trafficking, function and persistence. One of the initial obstacles that CAR T cells encounter is the abnormal tumour vasculature, which restricts efficient T cell infiltration, further compounded by a dense extracellular matrix. CAR T cells that do infiltrate the tumours are outnumbered by immunosuppressive cells such as regulatory T cells, myeloid-derived suppressor cells and tumour-associated macrophages. Additionally, tumour cells can contribute to CAR T cell resistance by upregulating immune checkpoint molecules, such as PDL1 and CTLA4, and engage in metabolic competition. In this Review, we discuss how cellular and non-cellular components of the TME impair CAR T cell therapy and consider potential strategies to improve CAR T cell therapies for solid tumours, either by reprogramming the TME or by engineering CAR T cells to resist the immunosuppressive effects of the TME. The tumour microenvironment (TME) poses a significant obstacle to the success of chimeric antigen receptor (CAR) T cell immunotherapy in solid tumours. Here, the authors detail how both cellular and non-cellular components of the TME contribute to tumour resistance against CAR T cell therapy, and explore emerging strategies aimed at overcoming these barriers in order to enhance the efficacy of CAR T cell therapy.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":"26 3","pages":"230-248"},"PeriodicalIF":60.9,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288399","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 : 2025-10-09DOI: 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}
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