Pub Date : 2025-08-07DOI: 10.1038/s41577-025-01207-9
Andrew C. Chan, Greg D. Martyn, Paul J. Carter
In 1975, Köhler and Milstein invented hybridoma technology for the generation of murine monoclonal antibodies with predetermined antigen-binding specificity. The transformative impact of monoclonal antibodies is demonstrated by their ubiquitous use as biomedical research reagents and the worldwide approval of at least 212 antibody therapeutics with tens of millions of patients treated to date. Advances in antibody technologies, such as humanization and robust methods for human antibody generation, mitigated the major limitations of murine antibodies as therapeutics. These technologies, combined with progress in biomanufacturing, helped to launch this modern era of antibody therapeutics. Beyond IgG, antibody therapeutics have blossomed into multiple alternative formats, including bispecific antibodies and antibody–drug conjugates. Additionally, antibody fragments have been developed as stand-alone therapeutics and to target cell therapies, notably chimeric antigen receptor T cells. These advances in antibody technologies, plus innovation enabling subcutaneous delivery, have improved the therapeutic benefits and convenience of antibody treatment for many patients. This concept is illustrated here by multiple generations of antibody therapeutics for human epidermal growth factor receptor 2 (HER2)+ cancers and B cell-targeted therapies for haematological cancers and immunological diseases. Finally, we opine briefly on some of the many promising future directions with antibody therapeutics, including the application of artificial intelligence for antibody identification and multi-parameter optimization. Fifty years ago, Köhler and Milstein introduced the world to hybridoma technology for the generation of monoclonal antibodies. Scientists have subsequently built upon this seminal discovery to develop antibody-based therapies for numerous diseases, with millions of patients benefiting from such drugs. To mark 50 years of monoclonal antibodies, this Review from Chan, Martyn and Carter provides an overview of how antibody engineering strategies have continued to improve antibody-based therapeutics, chiefly focusing on antibody-mediated targeting of B cells and also human epidermal growth factor receptor 2 (HER2)+ cancers. The authors also highlight the promise of emerging tools, including artificial intelligence, for development of the next generation of antibody-based therapeutics.
{"title":"Fifty years of monoclonals: the past, present and future of antibody therapeutics","authors":"Andrew C. Chan, Greg D. Martyn, Paul J. Carter","doi":"10.1038/s41577-025-01207-9","DOIUrl":"10.1038/s41577-025-01207-9","url":null,"abstract":"In 1975, Köhler and Milstein invented hybridoma technology for the generation of murine monoclonal antibodies with predetermined antigen-binding specificity. The transformative impact of monoclonal antibodies is demonstrated by their ubiquitous use as biomedical research reagents and the worldwide approval of at least 212 antibody therapeutics with tens of millions of patients treated to date. Advances in antibody technologies, such as humanization and robust methods for human antibody generation, mitigated the major limitations of murine antibodies as therapeutics. These technologies, combined with progress in biomanufacturing, helped to launch this modern era of antibody therapeutics. Beyond IgG, antibody therapeutics have blossomed into multiple alternative formats, including bispecific antibodies and antibody–drug conjugates. Additionally, antibody fragments have been developed as stand-alone therapeutics and to target cell therapies, notably chimeric antigen receptor T cells. These advances in antibody technologies, plus innovation enabling subcutaneous delivery, have improved the therapeutic benefits and convenience of antibody treatment for many patients. This concept is illustrated here by multiple generations of antibody therapeutics for human epidermal growth factor receptor 2 (HER2)+ cancers and B cell-targeted therapies for haematological cancers and immunological diseases. Finally, we opine briefly on some of the many promising future directions with antibody therapeutics, including the application of artificial intelligence for antibody identification and multi-parameter optimization. Fifty years ago, Köhler and Milstein introduced the world to hybridoma technology for the generation of monoclonal antibodies. Scientists have subsequently built upon this seminal discovery to develop antibody-based therapies for numerous diseases, with millions of patients benefiting from such drugs. To mark 50 years of monoclonal antibodies, this Review from Chan, Martyn and Carter provides an overview of how antibody engineering strategies have continued to improve antibody-based therapeutics, chiefly focusing on antibody-mediated targeting of B cells and also human epidermal growth factor receptor 2 (HER2)+ cancers. The authors also highlight the promise of emerging tools, including artificial intelligence, for development of the next generation of antibody-based therapeutics.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":"25 10","pages":"745-765"},"PeriodicalIF":60.9,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792354","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 : 2025-07-29DOI: 10.1038/s41577-025-01206-w
Dina Hochhauser, Rotem Sorek
The cell-autonomous innate immune system is responsible for sensing and mitigating viral infection at the level of individual cells. Many of the mechanisms used by the cell-autonomous innate immune system in eukaryotic cells are ancient and have evolutionary roots in bacterial systems that defend against phage infection. Studies from recent years have shown that modification of the free nucleotide pool is central to many of these conserved immune mechanisms. In this Review, we explain how immune pathways manipulate the available pool of nucleotides to deprive viruses of molecules essential for their replication, how immune proteins chemically modify nucleotides to generate immune signalling molecules, and how cell-autonomous innate immune mechanisms produce altered nucleotides that poison viral replication. We also discuss the mechanisms used by viruses to antagonize nucleotide-based immunity. Finally, we explore the evolutionary logic of using nucleotides as building blocks for immune responses.
{"title":"Manipulation of the nucleotide pool in human, bacterial and plant immunity","authors":"Dina Hochhauser, Rotem Sorek","doi":"10.1038/s41577-025-01206-w","DOIUrl":"https://doi.org/10.1038/s41577-025-01206-w","url":null,"abstract":"<p>The cell-autonomous innate immune system is responsible for sensing and mitigating viral infection at the level of individual cells. Many of the mechanisms used by the cell-autonomous innate immune system in eukaryotic cells are ancient and have evolutionary roots in bacterial systems that defend against phage infection. Studies from recent years have shown that modification of the free nucleotide pool is central to many of these conserved immune mechanisms. In this Review, we explain how immune pathways manipulate the available pool of nucleotides to deprive viruses of molecules essential for their replication, how immune proteins chemically modify nucleotides to generate immune signalling molecules, and how cell-autonomous innate immune mechanisms produce altered nucleotides that poison viral replication. We also discuss the mechanisms used by viruses to antagonize nucleotide-based immunity. Finally, we explore the evolutionary logic of using nucleotides as building blocks for immune responses.</p>","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":"709 1","pages":""},"PeriodicalIF":100.3,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719705","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 : 2025-07-28DOI: 10.1038/s41577-025-01217-7
Yvonne Bordon
Exercise promotes changes in the gut microbiota that enhance anti-tumour T cell responses.
运动促进肠道微生物群的变化，增强抗肿瘤T细胞反应。
{"title":"Exercise induces metabolic changes in the gut microbiota that enhance anti-tumour T cell responses","authors":"Yvonne Bordon","doi":"10.1038/s41577-025-01217-7","DOIUrl":"10.1038/s41577-025-01217-7","url":null,"abstract":"Exercise promotes changes in the gut microbiota that enhance anti-tumour T cell responses.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":"25 9","pages":"634-634"},"PeriodicalIF":60.9,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144715334","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 : 2025-07-24DOI: 10.1038/s41577-025-01203-z
Enzo Z. Poirier
Stem cells maintain tissue architecture by replacing differentiated cells at steady state and upon injury. Implementing this cornerstone role requires protection of stem cells from pathogens and from the toxic effects of immune system activation. However, the pro-inflammatory innate immune mechanisms that protect differentiated cells from infection are poorly functional in stem cells. Instead, stem cells employ other specific defence mechanisms, such as antiviral RNA interference. At steady state, the proliferation and differentiation of tissue stem cells is regulated by multiple cell types, including immune cells. Following sterile tissue injury or during infection, the immune response — in addition to controlling pathogens and clearing cell debris — orchestrates tissue repair by fine-tuning stem cell activity, through direct cell–cell contacts and via inflammatory mediators such as cytokines. There is thus stem–immune cross-talk that is fundamental to the maintenance of tissue homeostasis. Inflammageing, which is defined as the age-driven elevation of inflammation and is associated with an altered immune cell composition, profoundly affects this stem–immune cross-talk, impacting the ability to repair tissues and participating in ageing of the whole organism. This Review by Poirier highlights the intrinsic mechanisms that protect stem cells from infection. The author also explains how stem cell populations in different tissue sites respond to infection or injury to protect tissue integrity, and the impact of inflammageing on these processes.
{"title":"How stem cells respond to infection, inflammation and ageing","authors":"Enzo Z. Poirier","doi":"10.1038/s41577-025-01203-z","DOIUrl":"10.1038/s41577-025-01203-z","url":null,"abstract":"Stem cells maintain tissue architecture by replacing differentiated cells at steady state and upon injury. Implementing this cornerstone role requires protection of stem cells from pathogens and from the toxic effects of immune system activation. However, the pro-inflammatory innate immune mechanisms that protect differentiated cells from infection are poorly functional in stem cells. Instead, stem cells employ other specific defence mechanisms, such as antiviral RNA interference. At steady state, the proliferation and differentiation of tissue stem cells is regulated by multiple cell types, including immune cells. Following sterile tissue injury or during infection, the immune response — in addition to controlling pathogens and clearing cell debris — orchestrates tissue repair by fine-tuning stem cell activity, through direct cell–cell contacts and via inflammatory mediators such as cytokines. There is thus stem–immune cross-talk that is fundamental to the maintenance of tissue homeostasis. Inflammageing, which is defined as the age-driven elevation of inflammation and is associated with an altered immune cell composition, profoundly affects this stem–immune cross-talk, impacting the ability to repair tissues and participating in ageing of the whole organism. This Review by Poirier highlights the intrinsic mechanisms that protect stem cells from infection. The author also explains how stem cell populations in different tissue sites respond to infection or injury to protect tissue integrity, and the impact of inflammageing on these processes.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":"25 12","pages":"900-911"},"PeriodicalIF":60.9,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701339","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 : 2025-07-24DOI: 10.1038/s41577-025-01212-y
Qisi Zhang, Longlong Si
In this Tools of the Trade article, Qisi Zhang and Longlong Si describe a method for generating live attenuated vaccines that involves targeting viruses to the host cells’ protein degradation machinery, which attenuates the virus within the host and also enhances viral antigen presentation.
{"title":"Live vaccine development through targeted protein degradation","authors":"Qisi Zhang, Longlong Si","doi":"10.1038/s41577-025-01212-y","DOIUrl":"10.1038/s41577-025-01212-y","url":null,"abstract":"In this Tools of the Trade article, Qisi Zhang and Longlong Si describe a method for generating live attenuated vaccines that involves targeting viruses to the host cells’ protein degradation machinery, which attenuates the virus within the host and also enhances viral antigen presentation.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":"25 9","pages":"633-633"},"PeriodicalIF":60.9,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701340","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 : 2025-07-23DOI: 10.1038/s41577-025-01216-8
Adam J. Grippin, Wen Jiang
A recent preprint by Floyd et al. presents the most comprehensive mapping to date of the human lymphocyte ‘surfaceome’.
Floyd等人最近的预印本展示了迄今为止最全面的人类淋巴细胞“表面体”图谱。
{"title":"Mitochondrial proteins go public and novel interactions: insights from surfaceome mapping","authors":"Adam J. Grippin, Wen Jiang","doi":"10.1038/s41577-025-01216-8","DOIUrl":"10.1038/s41577-025-01216-8","url":null,"abstract":"A recent preprint by Floyd et al. presents the most comprehensive mapping to date of the human lymphocyte ‘surfaceome’.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":"25 9","pages":"636-636"},"PeriodicalIF":60.9,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693220","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 : 2025-07-22DOI: 10.1038/s41577-025-01200-2
Deborah M. Nash, Joanna L. Giles
Uterine inflammation encompasses several conditions, including endometritis, which is a local innate immune response, usually to bacteria. Endometritis is an important veterinary and medical problem that can result in infertility and/or recurrent pregnancy loss. This Review aims to summarize animal models that can be used to uncover the immune pathways responsible for uterine inflammation and their value for screening novel, putative therapies. We discuss large animal models of endometritis, particularly the well-used bovine system and the value that may be added by further developing porcine systems. Animal cells and tissue explants can be ethically sourced, and these models can replace or reduce the need for live animal studies and overcome the practical issues of harvesting endometrial material from women. We explain how these models of endometritis show great potential for advancing our understanding of the immune dysfunction underlying susceptibility to the condition, and for early-stage drug discovery. Endometritis can cause infertility and recurrent pregnancy loss and is an important medical and veterinary issue. Here, Nash and Giles provide an overview of the various models that can be used to study uterine inflammation and discuss their value for developing new therapies.
{"title":"Uterine inflammation and lessons from large animal models of endometritis","authors":"Deborah M. Nash, Joanna L. Giles","doi":"10.1038/s41577-025-01200-2","DOIUrl":"10.1038/s41577-025-01200-2","url":null,"abstract":"Uterine inflammation encompasses several conditions, including endometritis, which is a local innate immune response, usually to bacteria. Endometritis is an important veterinary and medical problem that can result in infertility and/or recurrent pregnancy loss. This Review aims to summarize animal models that can be used to uncover the immune pathways responsible for uterine inflammation and their value for screening novel, putative therapies. We discuss large animal models of endometritis, particularly the well-used bovine system and the value that may be added by further developing porcine systems. Animal cells and tissue explants can be ethically sourced, and these models can replace or reduce the need for live animal studies and overcome the practical issues of harvesting endometrial material from women. We explain how these models of endometritis show great potential for advancing our understanding of the immune dysfunction underlying susceptibility to the condition, and for early-stage drug discovery. Endometritis can cause infertility and recurrent pregnancy loss and is an important medical and veterinary issue. Here, Nash and Giles provide an overview of the various models that can be used to study uterine inflammation and discuss their value for developing new therapies.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":"25 12","pages":"934-946"},"PeriodicalIF":60.9,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677305","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 : 2025-07-17DOI: 10.1038/s41577-025-01213-x
Siu Ling Tai, Arthur Mortha
A preprint by Wu et al. identifies BRD4 as a sensor of pH, with notable implications for the regulation of inflammatory genes.
Wu等人的预印本将BRD4鉴定为pH传感器，对炎症基因的调节具有重要意义。
{"title":"BRD4 acts as a pH sensor to tune inflammation","authors":"Siu Ling Tai, Arthur Mortha","doi":"10.1038/s41577-025-01213-x","DOIUrl":"10.1038/s41577-025-01213-x","url":null,"abstract":"A preprint by Wu et al. identifies BRD4 as a sensor of pH, with notable implications for the regulation of inflammatory genes.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":"25 9","pages":"635-635"},"PeriodicalIF":60.9,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652570","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 : 2025-07-10DOI: 10.1038/s41577-025-01199-6
Alexander Leunig, Matteo Gianeselli, Scott J. Russo, Filip K. Swirski
Connections between the nervous and immune systems are increasingly recognized as central to brain–body physiology. In this Review, we examine how these systems collaborate to detect and respond to both internal and external stimuli — such as psychological stress, circadian cues, infection, and tissue injury. Rather than operating in isolation, the nervous and immune systems form an integrated network that is more than the sum of its parts. They share a common architecture and vocabulary, enabling bidirectional connection and communication that modulate immune cell characteristics throughout the body. We review immune–nervous interactions within two complementary frameworks: first, a spatial framework that distinguishes communication in the brain, communication within peripheral organs, and communication across distance; and second, a temporal framework that maps nervous system influence across the operational lifespan of the immune system — specifically focusing on how the nervous system impacts immune cell development, distribution, and execution of functions. Finally, we highlight key tools, clinical applications, and questions for future research on how both systems coordinate to respond to somatic and environmental stressors. Here, Swirski and colleagues explore how the nervous and immune systems connect and collaborate to respond to internal and external stimuli. In particular, they consider how the exchange of information between both systems is vital for host physiology, in the context of both health and disease.
{"title":"Connection and communication between the nervous and immune systems","authors":"Alexander Leunig, Matteo Gianeselli, Scott J. Russo, Filip K. Swirski","doi":"10.1038/s41577-025-01199-6","DOIUrl":"10.1038/s41577-025-01199-6","url":null,"abstract":"Connections between the nervous and immune systems are increasingly recognized as central to brain–body physiology. In this Review, we examine how these systems collaborate to detect and respond to both internal and external stimuli — such as psychological stress, circadian cues, infection, and tissue injury. Rather than operating in isolation, the nervous and immune systems form an integrated network that is more than the sum of its parts. They share a common architecture and vocabulary, enabling bidirectional connection and communication that modulate immune cell characteristics throughout the body. We review immune–nervous interactions within two complementary frameworks: first, a spatial framework that distinguishes communication in the brain, communication within peripheral organs, and communication across distance; and second, a temporal framework that maps nervous system influence across the operational lifespan of the immune system — specifically focusing on how the nervous system impacts immune cell development, distribution, and execution of functions. Finally, we highlight key tools, clinical applications, and questions for future research on how both systems coordinate to respond to somatic and environmental stressors. Here, Swirski and colleagues explore how the nervous and immune systems connect and collaborate to respond to internal and external stimuli. In particular, they consider how the exchange of information between both systems is vital for host physiology, in the context of both health and disease.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":"25 12","pages":"912-933"},"PeriodicalIF":60.9,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594069","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 : 2025-07-07DOI: 10.1038/s41577-025-01209-7
Lucy Bird
The antitumoural effects of BCG can be vastly improved by combining it with β-glucan. The combination therapy enhances granulopoiesis and trains neutrophils to resist conversion into a protumoural phenotype in a mouse model of bladder cancer.
{"title":"BCG plus β-glucan trains neutrophils to beat bladder cancer","authors":"Lucy Bird","doi":"10.1038/s41577-025-01209-7","DOIUrl":"10.1038/s41577-025-01209-7","url":null,"abstract":"The antitumoural effects of BCG can be vastly improved by combining it with β-glucan. The combination therapy enhances granulopoiesis and trains neutrophils to resist conversion into a protumoural phenotype in a mouse model of bladder cancer.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":"25 8","pages":"556-556"},"PeriodicalIF":60.9,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568952","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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