Pub Date : 2025-11-13DOI: 10.1038/s41422-025-01197-2
Martina Wallace, Ramya S Kuna, Christian M Metallo
{"title":"Branched-chain fatty acids fire up the peroxisome.","authors":"Martina Wallace, Ramya S Kuna, Christian M Metallo","doi":"10.1038/s41422-025-01197-2","DOIUrl":"https://doi.org/10.1038/s41422-025-01197-2","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":" ","pages":""},"PeriodicalIF":25.9,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145511856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The limited success of current immunotherapies emphasizes the need for new targets and combination treatments. V-domain Ig suppressor of T cell activation (VISTA) is a promising immune checkpoint target in cancer immunotherapy, but its regulatory mechanism is poorly understood. Through CRISPR knockout screening and proteomic analysis, we identify tripartite motif containing 25 (TRIM25) as a positive regulator for VISTA largely through antagonizing its degradation signaling. Moreover, ERK-mediated phosphorylation of VISTA at Thr284 enhances its interaction with TRIM25, leading to VISTA stabilization. A VISTA-derived phospho-peptide competitively disrupts TRIM25–VISTA interaction, thereby reducing VISTA expression and potentiating the anti-tumor efficacy of PD-1/PD-L1 blockade. Moreover, single-cell RNA sequencing analysis shows that tumor-infiltrating cytotoxic CD8+ T cells are increased in mice with T cell-specific knockout of Trim25. Of note, genetic ablation of Trim25 in T cells not only improves anti-PD-L1 immunotherapy, but also significantly ameliorates CAR T anti-tumor activity in various mouse tumor models. Collectively, this study unveils a mechanism for VISTA regulation in T cells and highlights targeting TRIM25–VISTA as a potential strategy to enhance tumor immunotherapy.
目前免疫疗法的有限成功强调需要新的靶点和联合治疗。V-domain Ig suppressor of T cell activation （VISTA）是肿瘤免疫治疗中一个很有前景的免疫检查点靶点，但其调控机制尚不清楚。通过CRISPR敲除筛选和蛋白质组学分析，我们确定tripartite motif containing 25 （TRIM25）主要通过拮抗其降解信号传导而成为VISTA的正调控因子。此外，erk介导的VISTA Thr284位点磷酸化增强了它与TRIM25的相互作用，导致VISTA稳定。VISTA衍生的磷酸化肽竞争性地破坏TRIM25-VISTA相互作用，从而降低VISTA表达并增强PD-1/PD-L1阻断的抗肿瘤功效。此外，单细胞RNA测序分析显示，在T细胞特异性敲除Trim25的小鼠中，肿瘤浸润性细胞毒性CD8+ T细胞增加。值得注意的是，基因消融T细胞中的Trim25不仅可以改善抗pd - l1免疫治疗，还可以显著改善各种小鼠肿瘤模型中的CAR - T抗肿瘤活性。总的来说，这项研究揭示了VISTA在T细胞中的调节机制，并强调靶向TRIM25-VISTA是增强肿瘤免疫治疗的潜在策略。
{"title":"Destruction of VISTA by TRIM25 ablation in T cells potentiates cancer immunotherapy","authors":"Yishuang Sun, Zijian Zhang, Haiou Li, Xia Bu, Li Chen, Xiyong Wang, Lifang Fan, Baoxiang Chen, Lijun Kong, Panpan Dai, Wenjing Song, Xiangling Xiao, Jie Shi, Bolin Xiang, Chuan He, Yingmeng Yao, Wenjun Xiong, Haisheng Yu, Congqing Jiang, Qun Qian, Hudan Liu, Sufang Tian, Guoliang Qing, Zhiyong Yang, Wenyi Wei, Gordon J. Freeman, Haichuan Zhu, Jinfang Zhang","doi":"10.1038/s41422-025-01186-5","DOIUrl":"10.1038/s41422-025-01186-5","url":null,"abstract":"The limited success of current immunotherapies emphasizes the need for new targets and combination treatments. V-domain Ig suppressor of T cell activation (VISTA) is a promising immune checkpoint target in cancer immunotherapy, but its regulatory mechanism is poorly understood. Through CRISPR knockout screening and proteomic analysis, we identify tripartite motif containing 25 (TRIM25) as a positive regulator for VISTA largely through antagonizing its degradation signaling. Moreover, ERK-mediated phosphorylation of VISTA at Thr284 enhances its interaction with TRIM25, leading to VISTA stabilization. A VISTA-derived phospho-peptide competitively disrupts TRIM25–VISTA interaction, thereby reducing VISTA expression and potentiating the anti-tumor efficacy of PD-1/PD-L1 blockade. Moreover, single-cell RNA sequencing analysis shows that tumor-infiltrating cytotoxic CD8+ T cells are increased in mice with T cell-specific knockout of Trim25. Of note, genetic ablation of Trim25 in T cells not only improves anti-PD-L1 immunotherapy, but also significantly ameliorates CAR T anti-tumor activity in various mouse tumor models. Collectively, this study unveils a mechanism for VISTA regulation in T cells and highlights targeting TRIM25–VISTA as a potential strategy to enhance tumor immunotherapy.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 12","pages":"1003-1020"},"PeriodicalIF":25.9,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145499518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-13DOI: 10.1038/s41422-025-01194-5
Li Chen, Xia Bu, Yishuang Sun, Daoyuan Huang, Yong Chen, Tao Hou, Xiaoping Hu, Jingchao Wang, Peiqiang Yan, Yihang Qi, Weiwei Jiang, Yan Xiong, Jing Liu, Yang Gao, Mengxi Huan, Bin Wang, Qianjia Liu, Xiaoming Dai, Fabin Dang, John M. Asara, Masanori Fujimoto, Hiroyuki Inuzuka, Jian Jin, Jinfang Zhang, Gordon J. Freeman, Wenyi Wei
Immune checkpoints serve as regulatory pathways that are essential for regulating immune response and homeostasis. As such, many components along the pathway have emerged as pivotal targets in cancer therapy. To overcome the treatment resistance and limited efficacy encountered by current immune checkpoint therapies, there is an urgent need for new immunotherapeutic targets and strategies. V-domain Ig suppressor of T cell activation (VISTA) is an immune checkpoint protein with a unique expression pattern and has emerged as a novel therapeutic target in anti-tumor immunotherapy; however, the precise role of VISTA and its regulatory mechanisms in tumor cells remain incompletely understood. Here, we identify a novel strategy targeting VISTA for cancer immunotherapy, enhancing therapeutic outcomes. Mechanistically, we show that VISTA undergoes anaphase-promoting complex/cyclosome (APC/C)/CDH1-mediated ubiquitination and subsequent proteasomal degradation, a process that can be reversed by the deubiquitinase USP2. Therapeutically, the USP2 inhibitor MS102 significantly reduces VISTA protein abundance in vitro and in vivo, enhances T cell responses, and synergizes with anti-PD-1 immunotherapy to improve survival in syngeneic mouse tumor models. Our findings reveal a regulatory network for VISTA stability control and support the combination of USP2 inhibitors with anti-PD-1 immunotherapy to enhance anti-tumor immune responses.
免疫检查点是调节免疫反应和体内平衡的重要途径。因此，该通路上的许多成分已成为癌症治疗的关键靶点。为了克服目前免疫检查点疗法所遇到的治疗耐药性和有限的疗效，迫切需要新的免疫治疗靶点和策略。V-domain Ig suppressor of T cell activation （VISTA）是一种具有独特表达模式的免疫检查点蛋白，已成为抗肿瘤免疫治疗的新靶点；然而，VISTA在肿瘤细胞中的确切作用及其调控机制尚不完全清楚。在这里，我们确定了一种针对VISTA的癌症免疫治疗新策略，提高了治疗效果。在机制上，我们发现VISTA经历了后期促进复合物/环体(APC/C)/ cdh1介导的泛素化和随后的蛋白酶体降解，这一过程可以通过去泛素酶USP2逆转。在治疗上，USP2抑制剂MS102在体外和体内显著降低VISTA蛋白丰度，增强T细胞反应，并与抗pd -1免疫疗法协同作用，提高同基因小鼠肿瘤模型的生存率。我们的研究结果揭示了VISTA稳定性控制的调控网络，并支持USP2抑制剂与抗pd -1免疫疗法联合使用以增强抗肿瘤免疫应答。
{"title":"Targeted destruction of VISTA boosts anti-tumor immunotherapy","authors":"Li Chen, Xia Bu, Yishuang Sun, Daoyuan Huang, Yong Chen, Tao Hou, Xiaoping Hu, Jingchao Wang, Peiqiang Yan, Yihang Qi, Weiwei Jiang, Yan Xiong, Jing Liu, Yang Gao, Mengxi Huan, Bin Wang, Qianjia Liu, Xiaoming Dai, Fabin Dang, John M. Asara, Masanori Fujimoto, Hiroyuki Inuzuka, Jian Jin, Jinfang Zhang, Gordon J. Freeman, Wenyi Wei","doi":"10.1038/s41422-025-01194-5","DOIUrl":"10.1038/s41422-025-01194-5","url":null,"abstract":"Immune checkpoints serve as regulatory pathways that are essential for regulating immune response and homeostasis. As such, many components along the pathway have emerged as pivotal targets in cancer therapy. To overcome the treatment resistance and limited efficacy encountered by current immune checkpoint therapies, there is an urgent need for new immunotherapeutic targets and strategies. V-domain Ig suppressor of T cell activation (VISTA) is an immune checkpoint protein with a unique expression pattern and has emerged as a novel therapeutic target in anti-tumor immunotherapy; however, the precise role of VISTA and its regulatory mechanisms in tumor cells remain incompletely understood. Here, we identify a novel strategy targeting VISTA for cancer immunotherapy, enhancing therapeutic outcomes. Mechanistically, we show that VISTA undergoes anaphase-promoting complex/cyclosome (APC/C)/CDH1-mediated ubiquitination and subsequent proteasomal degradation, a process that can be reversed by the deubiquitinase USP2. Therapeutically, the USP2 inhibitor MS102 significantly reduces VISTA protein abundance in vitro and in vivo, enhances T cell responses, and synergizes with anti-PD-1 immunotherapy to improve survival in syngeneic mouse tumor models. Our findings reveal a regulatory network for VISTA stability control and support the combination of USP2 inhibitors with anti-PD-1 immunotherapy to enhance anti-tumor immune responses.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 12","pages":"987-1002"},"PeriodicalIF":25.9,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145499485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-11DOI: 10.1038/s41422-025-01192-7
Sara Marchese, Andrea Mattevi
{"title":"Myeloperoxidase: one enzyme, two jobs.","authors":"Sara Marchese, Andrea Mattevi","doi":"10.1038/s41422-025-01192-7","DOIUrl":"https://doi.org/10.1038/s41422-025-01192-7","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":" ","pages":""},"PeriodicalIF":25.9,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145494753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-07DOI: 10.1038/s41422-025-01191-8
Huibing Zhang, Xueting Wang, Kun Xi, Qingya Shen, Jianheng Xue, Yanqing Zhu, Shao-Kun Zang, Tianqiang Yu, Dan-Dan Shen, Jia Guo, Li-Nan Chen, Su-Yu Ji, Jiao Qin, Yingjun Dong, Mingming Zhao, Ming Yang, Haijing Wu, Guoli Yang, Yan Zhang
Activation of the μ-opioid receptor (μOR) alleviates pain but also elicits adverse effects through diverse G proteins and β-arrestins. The structural details of μOR complexes with Gz and β-arrestins have not been determined, impeding a comprehensive understanding of μOR signaling plasticity. Here, we present the cryo-EM structures of the μOR–Gz and μOR–βarr1 complexes, revealing selective conformational preferences of μOR when engaged with specific downstream signaling transducers. Integrated receptor pharmacology, including high-resolution structural analysis, cell signaling assays, and molecular dynamics simulations, demonstrated that transmembrane helix 1 (TM1) acts as an allosteric regulator of μOR signaling bias through differential stabilization of the Gi-, Gz-, and βarr1-bound states. Mechanistically, outward TM1 displacement confers structural flexibility that promotes G protein recruitment, whereas inward TM1 retraction facilitates βarr1 recruitment by stabilizing the intracellular binding pocket through coordinated interactions with TM2, TM7, and helix8. Structural comparisons between the Gi-, Gz-, and βarr1-bound complexes identified a TM1-fusion pocket with significant implications for downstream signaling regulation. Overall, we demonstrate that the conformational and thermodynamic heterogeneity of TM1 allosterically drives the downstream signaling specificity and plasticity of μOR, thereby expanding the understanding of μOR signal transduction mechanisms and providing new avenues for the rational design of analgesics.
{"title":"The molecular basis of μ-opioid receptor signaling plasticity","authors":"Huibing Zhang, Xueting Wang, Kun Xi, Qingya Shen, Jianheng Xue, Yanqing Zhu, Shao-Kun Zang, Tianqiang Yu, Dan-Dan Shen, Jia Guo, Li-Nan Chen, Su-Yu Ji, Jiao Qin, Yingjun Dong, Mingming Zhao, Ming Yang, Haijing Wu, Guoli Yang, Yan Zhang","doi":"10.1038/s41422-025-01191-8","DOIUrl":"10.1038/s41422-025-01191-8","url":null,"abstract":"Activation of the μ-opioid receptor (μOR) alleviates pain but also elicits adverse effects through diverse G proteins and β-arrestins. The structural details of μOR complexes with Gz and β-arrestins have not been determined, impeding a comprehensive understanding of μOR signaling plasticity. Here, we present the cryo-EM structures of the μOR–Gz and μOR–βarr1 complexes, revealing selective conformational preferences of μOR when engaged with specific downstream signaling transducers. Integrated receptor pharmacology, including high-resolution structural analysis, cell signaling assays, and molecular dynamics simulations, demonstrated that transmembrane helix 1 (TM1) acts as an allosteric regulator of μOR signaling bias through differential stabilization of the Gi-, Gz-, and βarr1-bound states. Mechanistically, outward TM1 displacement confers structural flexibility that promotes G protein recruitment, whereas inward TM1 retraction facilitates βarr1 recruitment by stabilizing the intracellular binding pocket through coordinated interactions with TM2, TM7, and helix8. Structural comparisons between the Gi-, Gz-, and βarr1-bound complexes identified a TM1-fusion pocket with significant implications for downstream signaling regulation. Overall, we demonstrate that the conformational and thermodynamic heterogeneity of TM1 allosterically drives the downstream signaling specificity and plasticity of μOR, thereby expanding the understanding of μOR signal transduction mechanisms and providing new avenues for the rational design of analgesics.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 12","pages":"1021-1036"},"PeriodicalIF":25.9,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01191-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145457272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-23DOI: 10.1038/s41422-025-01189-2
Alicia De La Cruz, H. Peter Larsson
{"title":"KCNQ1 and PIP2: it takes two to tango","authors":"Alicia De La Cruz, H. Peter Larsson","doi":"10.1038/s41422-025-01189-2","DOIUrl":"10.1038/s41422-025-01189-2","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 12","pages":"922-923"},"PeriodicalIF":25.9,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01189-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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