Pub Date : 2026-01-06DOI: 10.1038/s41423-025-01372-w
Yuna Jo, So Min Lee, Changwan Hong
{"title":"From splicing noise to therapeutic signaling: RCAN1-4 as a neoepitope in glioblastoma.","authors":"Yuna Jo, So Min Lee, Changwan Hong","doi":"10.1038/s41423-025-01372-w","DOIUrl":"https://doi.org/10.1038/s41423-025-01372-w","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":19.8,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145910752","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}
Innate immunity in host cells must be rapidly activated to combat invading microbes. Upon RIG-I activation, the transcription of type I interferons is induced within one hour in virus-infected cells. Previous studies have shown that endogenous MAVS spreads signals via aggregation on the mitochondrial membrane, whereas truncated recombinant MAVS forms prion-like filaments in vitro. How MAVS transmits signals so quickly, and the molecular architecture of its membrane aggregates, remains elusive. Here, we report that activated MAVS forms fibrils encircling its resident mitochondrion or connecting neighboring mitochondria with a “ladder-like” structure, allowing the activation of dormant MAVS on encountered mitochondria. This “intermitochondrial activation” process promotes a rapid antiviral response in cells to overcome the immediate danger caused by viruses. Moreover, stuck MAVS fibrils between mitochondria have limited cytosolic protein access and thus relay signals poorly. This study demonstrated that prion-like MAVS fibrils cluster in mitochondria to ensure a rapid antiviral response.
{"title":"Prion-like MAVS fibrils stitch mitochondria to promote a rapid antiviral response","authors":"Xiaoyu Yu, Panpan Wang, Nanhai Zhou, Liyuan Zhang, Xiao Gong, Qiang Guo, Zhengfan Jiang","doi":"10.1038/s41423-025-01382-8","DOIUrl":"10.1038/s41423-025-01382-8","url":null,"abstract":"Innate immunity in host cells must be rapidly activated to combat invading microbes. Upon RIG-I activation, the transcription of type I interferons is induced within one hour in virus-infected cells. Previous studies have shown that endogenous MAVS spreads signals via aggregation on the mitochondrial membrane, whereas truncated recombinant MAVS forms prion-like filaments in vitro. How MAVS transmits signals so quickly, and the molecular architecture of its membrane aggregates, remains elusive. Here, we report that activated MAVS forms fibrils encircling its resident mitochondrion or connecting neighboring mitochondria with a “ladder-like” structure, allowing the activation of dormant MAVS on encountered mitochondria. This “intermitochondrial activation” process promotes a rapid antiviral response in cells to overcome the immediate danger caused by viruses. Moreover, stuck MAVS fibrils between mitochondria have limited cytosolic protein access and thus relay signals poorly. This study demonstrated that prion-like MAVS fibrils cluster in mitochondria to ensure a rapid antiviral response.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"23 2","pages":"204-219"},"PeriodicalIF":19.8,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145910708","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 : 2026-01-06DOI: 10.1038/s41423-025-01384-6
Lan Kang, Gregory F Sonnenberg
{"title":"Epigenetics control lineage decisions during hematopoiesis of innate lymphocytes.","authors":"Lan Kang, Gregory F Sonnenberg","doi":"10.1038/s41423-025-01384-6","DOIUrl":"https://doi.org/10.1038/s41423-025-01384-6","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":19.8,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145910727","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 : 2026-01-06DOI: 10.1038/s41423-025-01377-5
Vassilis Glaros, Nimmy Francis, Taras Kreslavsky
The distinctive feature of the adaptive immune system is its ability to generate immunological memory that can provide defense against subsequent infections. In the case of antibody-mediated immune responses, this memory comes in two cellular forms: plasma cells (PCs) and memory B cells (MBCs). PCs protect against reinfection by constitutively producing antibodies. The presence of a diverse pool of MBCs, which can expand and differentiate into PCs in secondary immune responses, is thought to be particularly important for defense against new pathogen variants. Recent studies have shown that the MBC compartment is far more heterogeneous than previously anticipated. This heterogeneity, among other factors, is shaped by their developmental pathway (germinal center (GC) vs non-GC-derived MBCs), the duration and strength of antigenic stimulation, anatomical and microanatomical localization, and the timing of generation in ontogeny. Combinations of these “layers” of MBC identities can define MBCs’ properties and their fate in recall responses. Here, we review the mechanisms underlying MBC differentiation, maintenance, and reactivation and explore how the layered identity of MBCs contributes to the functions of these cells.
{"title":"The multilayered identity of B cell memory","authors":"Vassilis Glaros, Nimmy Francis, Taras Kreslavsky","doi":"10.1038/s41423-025-01377-5","DOIUrl":"10.1038/s41423-025-01377-5","url":null,"abstract":"The distinctive feature of the adaptive immune system is its ability to generate immunological memory that can provide defense against subsequent infections. In the case of antibody-mediated immune responses, this memory comes in two cellular forms: plasma cells (PCs) and memory B cells (MBCs). PCs protect against reinfection by constitutively producing antibodies. The presence of a diverse pool of MBCs, which can expand and differentiate into PCs in secondary immune responses, is thought to be particularly important for defense against new pathogen variants. Recent studies have shown that the MBC compartment is far more heterogeneous than previously anticipated. This heterogeneity, among other factors, is shaped by their developmental pathway (germinal center (GC) vs non-GC-derived MBCs), the duration and strength of antigenic stimulation, anatomical and microanatomical localization, and the timing of generation in ontogeny. Combinations of these “layers” of MBC identities can define MBCs’ properties and their fate in recall responses. Here, we review the mechanisms underlying MBC differentiation, maintenance, and reactivation and explore how the layered identity of MBCs contributes to the functions of these cells.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"23 2","pages":"150-167"},"PeriodicalIF":19.8,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01377-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145910775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1038/s41423-025-01352-0
Li Luo, Yi Wang, Guofeng Fang, Jiang Chang, Xin Dai, Heng Gu, Yanmei Huang, Heather Miller, Yue Li, Ran Chen, Ju Liu, Yukai Jing, Panpan Jiang, Lu Yang, Qianglin Chen, Jingzhi Yang, Xi Luo, Danqing Kang, Qi Liu, Juan Lai, Pengwei Xu, Huawei Mao, Xiufen Hu, Xingrong Du, Jiahui Lei, Xiuran Tang, Weibing Kuang, Cheng Wu, Zhanguo Li, Zhenli Huang, Wanli Liu, Chaohong Liu
Melanoma Differentiation-Associated gene 5 (MDA5) serves as a pattern recognition receptor (PRR) that identifies pathogen-associated molecular patterns (PAMPs), making it instrumental in antiviral defense. However, its non-canonical role in adaptive immunity, particularly in regulating B-cell immune functions, is poorly characterized. Here, we demonstrate that MDA5 is critical for the marginal zone (MZ) B-cell differentiation, B-cell receptor (BCR) signal transduction, and cytoskeletal dynamics. We determined that the MDA5-NF-κB-DNM1 axis governs actin polymerization and that this impairment in Mda5 knockout (KO) B cells can be rescued by the treatment with the dynamin1 (DNM1) activator Bis-T-23. Furthermore, MDA5 deficiency induces metabolic perturbations in B cells, characterized by a reduced extracellular acidification rate (ECAR) and oxygen consumption rate (OCR), excessive reactive oxygen species (ROS) accumulation, and increased mitochondrial fission. Notably, taurine levels are decreased in Mda5 KO B cells, and in vitro taurine supplementation rescues impaired BCR signaling. Finally, MDA5-deficient mice exhibit a blunted humoral immune response. Overall, this study reveals the key functions and molecular mechanisms of MDA5 in B-cell differentiation, BCR signaling, and the humoral immune response.
黑色素瘤分化相关基因5 （MDA5）作为模式识别受体（PRR）识别病原体相关分子模式（PAMPs），使其在抗病毒防御中发挥重要作用。然而，其在适应性免疫中的非规范作用，特别是在调节b细胞免疫功能方面的作用，尚不清楚。在这里，我们证明MDA5对边缘区（MZ） b细胞分化、b细胞受体（BCR）信号转导和细胞骨架动力学至关重要。我们确定Mda5 - nf -κB-DNM1轴控制肌动蛋白聚合，并且Mda5敲除（KO） B细胞中的这种损伤可以通过dynamin1 （DNM1）激活剂Bis-T-23治疗而恢复。此外，MDA5缺乏诱导B细胞代谢紊乱，其特征是细胞外酸化率（ECAR）和耗氧率（OCR）降低，活性氧（ROS）积累过多，线粒体裂变增加。值得注意的是，Mda5 KO B细胞中的牛磺酸水平降低，体外补充牛磺酸可以挽救受损的BCR信号。最后，mda5缺陷小鼠表现出迟钝的体液免疫反应。总的来说，本研究揭示了MDA5在b细胞分化、BCR信号传导和体液免疫应答中的关键功能和分子机制。
{"title":"MDA5 regulates BCR signaling and B-cell function via NF-κB-mediated DNM1","authors":"Li Luo, Yi Wang, Guofeng Fang, Jiang Chang, Xin Dai, Heng Gu, Yanmei Huang, Heather Miller, Yue Li, Ran Chen, Ju Liu, Yukai Jing, Panpan Jiang, Lu Yang, Qianglin Chen, Jingzhi Yang, Xi Luo, Danqing Kang, Qi Liu, Juan Lai, Pengwei Xu, Huawei Mao, Xiufen Hu, Xingrong Du, Jiahui Lei, Xiuran Tang, Weibing Kuang, Cheng Wu, Zhanguo Li, Zhenli Huang, Wanli Liu, Chaohong Liu","doi":"10.1038/s41423-025-01352-0","DOIUrl":"10.1038/s41423-025-01352-0","url":null,"abstract":"Melanoma Differentiation-Associated gene 5 (MDA5) serves as a pattern recognition receptor (PRR) that identifies pathogen-associated molecular patterns (PAMPs), making it instrumental in antiviral defense. However, its non-canonical role in adaptive immunity, particularly in regulating B-cell immune functions, is poorly characterized. Here, we demonstrate that MDA5 is critical for the marginal zone (MZ) B-cell differentiation, B-cell receptor (BCR) signal transduction, and cytoskeletal dynamics. We determined that the MDA5-NF-κB-DNM1 axis governs actin polymerization and that this impairment in Mda5 knockout (KO) B cells can be rescued by the treatment with the dynamin1 (DNM1) activator Bis-T-23. Furthermore, MDA5 deficiency induces metabolic perturbations in B cells, characterized by a reduced extracellular acidification rate (ECAR) and oxygen consumption rate (OCR), excessive reactive oxygen species (ROS) accumulation, and increased mitochondrial fission. Notably, taurine levels are decreased in Mda5 KO B cells, and in vitro taurine supplementation rescues impaired BCR signaling. Finally, MDA5-deficient mice exhibit a blunted humoral immune response. Overall, this study reveals the key functions and molecular mechanisms of MDA5 in B-cell differentiation, BCR signaling, and the humoral immune response.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"23 2","pages":"168-185"},"PeriodicalIF":19.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145877815","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 : 2025-12-24DOI: 10.1038/s41423-025-01376-6
Kang Sun, Jia-xin Dong, Xin-tao Mao, Wen-ping Li, Yu Wang, Xiao-mei Teng, Dan-dan Liu, Bing Yang, Jiang-yan Zhong, Zhenya Shen, Yi-yuan Li, Jin Jin
The regenerative capacities of organs in adult mammals vary significantly. Unlike the liver, which possesses remarkable regenerative potential, the repair of cardiac injuries has long posed a critical medical challenge. Recent studies have highlighted the pivotal role of the immune microenvironment in repairing damage in these tissues, but the key cell types and their mechanisms of action remain incompletely understood. In this study, we established a model of concurrent physical trauma to the hearts and livers of adult mice, revealing that these two injured tissues drive distinct immune microenvironments. The liver primarily accumulates lymphocytes, whereas the heart recruits macrophages and neutrophils. Notably, CD160+CD8+ intraepithelial lymphocytes in the liver were found to suppress fibrosis postliver injury and mitigate cardiac fibrosis when delivered via hydrogel patches. Conversely, in response to heart trauma, recruited inflammatory macrophages not only express proinflammatory cytokines but also coexpress CCRL2. While CCRL2 did not directly alter the intensity of the inflammatory response, it facilitated fibroblast proliferation and migration through its interaction with Na+/K+-ATPase on fibroblasts. These findings elucidated the contrasting immune microenvironments between the heart and liver following injury and provided novel insights and strategies for diagnosing and treating cardiac diseases.
{"title":"CD160+ intraepithelial lymphocytes and CCRL2+ macrophages drive differential repair in cardiac and liver injuries","authors":"Kang Sun, Jia-xin Dong, Xin-tao Mao, Wen-ping Li, Yu Wang, Xiao-mei Teng, Dan-dan Liu, Bing Yang, Jiang-yan Zhong, Zhenya Shen, Yi-yuan Li, Jin Jin","doi":"10.1038/s41423-025-01376-6","DOIUrl":"10.1038/s41423-025-01376-6","url":null,"abstract":"The regenerative capacities of organs in adult mammals vary significantly. Unlike the liver, which possesses remarkable regenerative potential, the repair of cardiac injuries has long posed a critical medical challenge. Recent studies have highlighted the pivotal role of the immune microenvironment in repairing damage in these tissues, but the key cell types and their mechanisms of action remain incompletely understood. In this study, we established a model of concurrent physical trauma to the hearts and livers of adult mice, revealing that these two injured tissues drive distinct immune microenvironments. The liver primarily accumulates lymphocytes, whereas the heart recruits macrophages and neutrophils. Notably, CD160+CD8+ intraepithelial lymphocytes in the liver were found to suppress fibrosis postliver injury and mitigate cardiac fibrosis when delivered via hydrogel patches. Conversely, in response to heart trauma, recruited inflammatory macrophages not only express proinflammatory cytokines but also coexpress CCRL2. While CCRL2 did not directly alter the intensity of the inflammatory response, it facilitated fibroblast proliferation and migration through its interaction with Na+/K+-ATPase on fibroblasts. These findings elucidated the contrasting immune microenvironments between the heart and liver following injury and provided novel insights and strategies for diagnosing and treating cardiac diseases.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"23 2","pages":"186-203"},"PeriodicalIF":19.8,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145818306","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 : 2025-12-23DOI: 10.1038/s41423-025-01360-0
Zujian Xiong, Qinglin Kong, Bhuvitha Chagantipati, Amelia Stepniak, Ambika P. Jaswal, Chaim T. Sneiderman, Yuanyuan Han, Sydney A. Jackson, Rebecca A. Raphael, Wei Zhang, Muzi Li, Yapeng Chao, Bin Qin, Zeynep Dulkadir, Lance Schwegman, Yihao Zhang, Chloe Kuminkoski, Megan A. Mahlke, Poulomi Nath, Baoli Hu, Pascal O. Zinn, Megan Mantica, Sameer Agnihotri, Yael Nechemia-Arbely, Ian F. Pollack, Lora H. Rigatti, Thomas G. Forsthuber, Xuejun Li, Itay Raphael, Gary Kohanbash
Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options and a dismal prognosis. While immunotherapy has shown promise in treating some solid tumors, the treatment of GBM has been mostly unsuccessful because of a lack of targetable tumor antigens and high tumor heterogeneity. Here, we report RCAN1-4 as a novel tumor antigen derived from alternative splicing induced by the transcription factor C/EBPβ. Both C/EBPβ and RCAN1-4 are highly expressed in GBM and glioma stem cells as mesenchymal subtype hallmarks. We report an immunogenic HLA-A24-specific splicing junction epitope within exon 4 and exon 5 that is unique to RCAN1-4. This epitope was validated for its ability to stimulate T cell responses in HLA-A24+ donors and GBM patients, leading us to identify RCAN1-4-reactive T cell receptors (TCRs) for the construction of TCR-engineered T cells (TCR-T cells). Functional studies of TCR-Ts demonstrated the in vitro and in vivo killing of RCAN1-4pos GBM tumor cells, highlighting its potential as an immunotherapeutic target in mesenchymal GBM.
{"title":"C/EBPβ-induced alternative splicing of RCAN1 generates a potent TCR-T target in mesenchymal glioblastoma","authors":"Zujian Xiong, Qinglin Kong, Bhuvitha Chagantipati, Amelia Stepniak, Ambika P. Jaswal, Chaim T. Sneiderman, Yuanyuan Han, Sydney A. Jackson, Rebecca A. Raphael, Wei Zhang, Muzi Li, Yapeng Chao, Bin Qin, Zeynep Dulkadir, Lance Schwegman, Yihao Zhang, Chloe Kuminkoski, Megan A. Mahlke, Poulomi Nath, Baoli Hu, Pascal O. Zinn, Megan Mantica, Sameer Agnihotri, Yael Nechemia-Arbely, Ian F. Pollack, Lora H. Rigatti, Thomas G. Forsthuber, Xuejun Li, Itay Raphael, Gary Kohanbash","doi":"10.1038/s41423-025-01360-0","DOIUrl":"10.1038/s41423-025-01360-0","url":null,"abstract":"Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options and a dismal prognosis. While immunotherapy has shown promise in treating some solid tumors, the treatment of GBM has been mostly unsuccessful because of a lack of targetable tumor antigens and high tumor heterogeneity. Here, we report RCAN1-4 as a novel tumor antigen derived from alternative splicing induced by the transcription factor C/EBPβ. Both C/EBPβ and RCAN1-4 are highly expressed in GBM and glioma stem cells as mesenchymal subtype hallmarks. We report an immunogenic HLA-A24-specific splicing junction epitope within exon 4 and exon 5 that is unique to RCAN1-4. This epitope was validated for its ability to stimulate T cell responses in HLA-A24+ donors and GBM patients, leading us to identify RCAN1-4-reactive T cell receptors (TCRs) for the construction of TCR-engineered T cells (TCR-T cells). Functional studies of TCR-Ts demonstrated the in vitro and in vivo killing of RCAN1-4pos GBM tumor cells, highlighting its potential as an immunotherapeutic target in mesenchymal GBM.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"23 1","pages":"94-113"},"PeriodicalIF":19.8,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01360-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145818328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
T cells are central components of the adaptive immune system and play key roles in antitumor and antiviral responses. The diverse cell fates of T cells enable them to respond to different durations and strengths of antigen stimulation and various cytokine milieus in a context-dependent manner. During acute infection or vaccination, T cells differentiate into effector cells and later develop into memory cells after antigen clearance, which mediate immune protection against the same antigen. In contrast, during cancer and chronic infection, T cells fail to enter the canonical effector or memory cell differentiation path. Instead, antigen-specific T cells enter a dysfunctional, partially responsive state called exhaustion. Exhausted T cells are heterogeneous. A subset of exhausted T cells exhibits stem cell-like properties. These stem-like T cells sustain immunity through self-renewal and repopulation of terminally differentiated progenies. Stem-like properties are critical for T cell immunity induced by immunotherapy. This review summarizes recent advances in understanding the molecular mechanisms controlling the exhaustion and stemness of T cells and explores the potential of rewiring these circuits to increase the efficiency of T-cell-based immunotherapy.
{"title":"Regulation of T cell exhaustion and stemness: molecular mechanisms and implications for cancer immunotherapy","authors":"Zeyu Chen, Ziang Zhu, Taidou Hu, Chen Yao, Tuoqi Wu","doi":"10.1038/s41423-025-01378-4","DOIUrl":"10.1038/s41423-025-01378-4","url":null,"abstract":"T cells are central components of the adaptive immune system and play key roles in antitumor and antiviral responses. The diverse cell fates of T cells enable them to respond to different durations and strengths of antigen stimulation and various cytokine milieus in a context-dependent manner. During acute infection or vaccination, T cells differentiate into effector cells and later develop into memory cells after antigen clearance, which mediate immune protection against the same antigen. In contrast, during cancer and chronic infection, T cells fail to enter the canonical effector or memory cell differentiation path. Instead, antigen-specific T cells enter a dysfunctional, partially responsive state called exhaustion. Exhausted T cells are heterogeneous. A subset of exhausted T cells exhibits stem cell-like properties. These stem-like T cells sustain immunity through self-renewal and repopulation of terminally differentiated progenies. Stem-like properties are critical for T cell immunity induced by immunotherapy. This review summarizes recent advances in understanding the molecular mechanisms controlling the exhaustion and stemness of T cells and explores the potential of rewiring these circuits to increase the efficiency of T-cell-based immunotherapy.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"23 1","pages":"1-14"},"PeriodicalIF":19.8,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01378-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145780385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-10DOI: 10.1038/s41423-025-01373-9
Patricia Hernández-López, Caterina Riillo, Laia Gasull-Celades, Jairo G. E. Lommen, Sabine Heijhuurs, Jiali Zheng, Sascha van Bruggen, Marina Zintchenko, Simon M. Brandl, Susana Minguet, Jürgen Kuball, Dennis X. Beringer
T-cell-based therapies have shown remarkable success in combatting hematologic malignancies; however, their efficacy in solid tumors is hindered by the immunosuppressive microenvironment and restricted antigen availability. The use of chimeric costimulatory receptors (CCRs) has emerged as a strategy to improve T-cell function. However, most designs target antigens distinct from the primary antigen receptor, complicating their application across heterogeneous tumors. Here, we characterized the molecular requirements for a platform enabling costimulation in engineered T cells on the basis of dual targeting of a single antigen via a TCR and a CCR. We applied this strategy to the stress ligand BTN3A, which is broadly expressed in solid tumors and is a part of the antigen complex recognized by the γ9δ2TCR. Through structural modeling, alanine scanning, and antibody screening, we determined that 103-4-1BB, a BTN3A-specific CCR, bound to an epitope on BTN3A that was distinct from the γ9δ2TCR epitope. This epitope separation is critical for enabling synergistic coengagement of a single antigen, and the resulting increase in T-cell activation requires both γ9δ2TCR signaling and the trans-acting functionality of the anti-BTN3A-CCR. Moreover, the extracellular domain of 103-4-1BB stabilized T-cell–tumor cell interactions and increased γ9δ2TCR sensitivity, whereas its intracellular 4-1BB signaling domain drove robust proliferation, improved T-cell fitness, and mediated potent tumor control in vivo. Notably, cis-binding of the CCR to BTN3A on engineered T cells promoted survival in the absence of tumor cells, while transbinding to tumor-expressed BTN3A was required for infiltration, tumor clearance, and memory formation. These findings establish a modular framework for designing cis/trans-active CCRs that enhance T-cell function through single-antigen dual engagement, enabling broadly applicable strategies to improve solid tumor immunotherapy.
{"title":"Cis- and trans-binding chimeric costimulatory receptors enhance T-cell fitness and tumor control","authors":"Patricia Hernández-López, Caterina Riillo, Laia Gasull-Celades, Jairo G. E. Lommen, Sabine Heijhuurs, Jiali Zheng, Sascha van Bruggen, Marina Zintchenko, Simon M. Brandl, Susana Minguet, Jürgen Kuball, Dennis X. Beringer","doi":"10.1038/s41423-025-01373-9","DOIUrl":"10.1038/s41423-025-01373-9","url":null,"abstract":"T-cell-based therapies have shown remarkable success in combatting hematologic malignancies; however, their efficacy in solid tumors is hindered by the immunosuppressive microenvironment and restricted antigen availability. The use of chimeric costimulatory receptors (CCRs) has emerged as a strategy to improve T-cell function. However, most designs target antigens distinct from the primary antigen receptor, complicating their application across heterogeneous tumors. Here, we characterized the molecular requirements for a platform enabling costimulation in engineered T cells on the basis of dual targeting of a single antigen via a TCR and a CCR. We applied this strategy to the stress ligand BTN3A, which is broadly expressed in solid tumors and is a part of the antigen complex recognized by the γ9δ2TCR. Through structural modeling, alanine scanning, and antibody screening, we determined that 103-4-1BB, a BTN3A-specific CCR, bound to an epitope on BTN3A that was distinct from the γ9δ2TCR epitope. This epitope separation is critical for enabling synergistic coengagement of a single antigen, and the resulting increase in T-cell activation requires both γ9δ2TCR signaling and the trans-acting functionality of the anti-BTN3A-CCR. Moreover, the extracellular domain of 103-4-1BB stabilized T-cell–tumor cell interactions and increased γ9δ2TCR sensitivity, whereas its intracellular 4-1BB signaling domain drove robust proliferation, improved T-cell fitness, and mediated potent tumor control in vivo. Notably, cis-binding of the CCR to BTN3A on engineered T cells promoted survival in the absence of tumor cells, while transbinding to tumor-expressed BTN3A was required for infiltration, tumor clearance, and memory formation. These findings establish a modular framework for designing cis/trans-active CCRs that enhance T-cell function through single-antigen dual engagement, enabling broadly applicable strategies to improve solid tumor immunotherapy.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"23 1","pages":"79-93"},"PeriodicalIF":19.8,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145720873","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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