Sai Xiao, Songqi Duan, Yaqun Hong, Jianying Zhang, Shoubao Ma, Michael A. Caligiuri, Jianhua Yu
{"title":"YTHDF2缺失可增强Th9编程和CAR-Th9细胞抗肿瘤效果。","authors":"Sai Xiao, Songqi Duan, Yaqun Hong, Jianying Zhang, Shoubao Ma, Michael A. Caligiuri, Jianhua Yu","doi":"10.1038/s41590-025-02235-2","DOIUrl":null,"url":null,"abstract":"CD4+ T cells differentiate into various subsets, including T helper 1 (Th1), Th2, Th9, Th17 and regulatory T (Treg) cells, which are essential for immune responses and cancer immunotherapy. However, the role of RNA N6-methyladenosine (m6A) modification in this differentiation is unclear. Here we show that YTHDF2, an important m6A reader protein known to destabilize m6A-modified mRNA, negatively regulates Th9 cell differentiation. Ablation of Ythdf2 in both mouse and human naive CD4+ T cells promotes Th9 differentiation by stabilizing Gata3 and Smad3 mRNA under interleukin-4 (IL-4) and transforming growth factor β (TGF-β) signaling, respectively. Ythdf2-deficient Th9 cells produce increased amounts of IL-9 and IL-21, leading to increased tumor infiltration and cytotoxicity by CD8+ T cells and natural killer (NK) cells, thereby improving antitumor activity compared with wild-type Th9 cells. Moreover, YTHDF2 depletion in CAR-Th9 cells enhances their immune activation, reduces their terminal differentiation and augments their antitumor efficacy. Targeting YTHDF2 is thereby a promising strategy to enhance Th9 and CAR-Th9 cell-based cancer immunotherapies. The authors show that the m6A reader protein YTHDF2 negatively regulates Th9 cell differentiation and function. Ablation of YTHDF2 promotes antigen-specific Th9 cell and CAR-Th9 cell antitumor activity in solid tumors.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 9","pages":"1501-1515"},"PeriodicalIF":27.6000,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Loss of YTHDF2 enhances Th9 programming and CAR-Th9 cell antitumor efficacy\",\"authors\":\"Sai Xiao, Songqi Duan, Yaqun Hong, Jianying Zhang, Shoubao Ma, Michael A. Caligiuri, Jianhua Yu\",\"doi\":\"10.1038/s41590-025-02235-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"CD4+ T cells differentiate into various subsets, including T helper 1 (Th1), Th2, Th9, Th17 and regulatory T (Treg) cells, which are essential for immune responses and cancer immunotherapy. However, the role of RNA N6-methyladenosine (m6A) modification in this differentiation is unclear. Here we show that YTHDF2, an important m6A reader protein known to destabilize m6A-modified mRNA, negatively regulates Th9 cell differentiation. Ablation of Ythdf2 in both mouse and human naive CD4+ T cells promotes Th9 differentiation by stabilizing Gata3 and Smad3 mRNA under interleukin-4 (IL-4) and transforming growth factor β (TGF-β) signaling, respectively. Ythdf2-deficient Th9 cells produce increased amounts of IL-9 and IL-21, leading to increased tumor infiltration and cytotoxicity by CD8+ T cells and natural killer (NK) cells, thereby improving antitumor activity compared with wild-type Th9 cells. Moreover, YTHDF2 depletion in CAR-Th9 cells enhances their immune activation, reduces their terminal differentiation and augments their antitumor efficacy. Targeting YTHDF2 is thereby a promising strategy to enhance Th9 and CAR-Th9 cell-based cancer immunotherapies. The authors show that the m6A reader protein YTHDF2 negatively regulates Th9 cell differentiation and function. Ablation of YTHDF2 promotes antigen-specific Th9 cell and CAR-Th9 cell antitumor activity in solid tumors.\",\"PeriodicalId\":19032,\"journal\":{\"name\":\"Nature Immunology\",\"volume\":\"26 9\",\"pages\":\"1501-1515\"},\"PeriodicalIF\":27.6000,\"publicationDate\":\"2025-08-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature Immunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.nature.com/articles/s41590-025-02235-2\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Immunology","FirstCategoryId":"3","ListUrlMain":"https://www.nature.com/articles/s41590-025-02235-2","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
Loss of YTHDF2 enhances Th9 programming and CAR-Th9 cell antitumor efficacy
CD4+ T cells differentiate into various subsets, including T helper 1 (Th1), Th2, Th9, Th17 and regulatory T (Treg) cells, which are essential for immune responses and cancer immunotherapy. However, the role of RNA N6-methyladenosine (m6A) modification in this differentiation is unclear. Here we show that YTHDF2, an important m6A reader protein known to destabilize m6A-modified mRNA, negatively regulates Th9 cell differentiation. Ablation of Ythdf2 in both mouse and human naive CD4+ T cells promotes Th9 differentiation by stabilizing Gata3 and Smad3 mRNA under interleukin-4 (IL-4) and transforming growth factor β (TGF-β) signaling, respectively. Ythdf2-deficient Th9 cells produce increased amounts of IL-9 and IL-21, leading to increased tumor infiltration and cytotoxicity by CD8+ T cells and natural killer (NK) cells, thereby improving antitumor activity compared with wild-type Th9 cells. Moreover, YTHDF2 depletion in CAR-Th9 cells enhances their immune activation, reduces their terminal differentiation and augments their antitumor efficacy. Targeting YTHDF2 is thereby a promising strategy to enhance Th9 and CAR-Th9 cell-based cancer immunotherapies. The authors show that the m6A reader protein YTHDF2 negatively regulates Th9 cell differentiation and function. Ablation of YTHDF2 promotes antigen-specific Th9 cell and CAR-Th9 cell antitumor activity in solid tumors.
期刊介绍:
Nature Immunology is a monthly journal that publishes the highest quality research in all areas of immunology. The editorial decisions are made by a team of full-time professional editors. The journal prioritizes work that provides translational and/or fundamental insight into the workings of the immune system. It covers a wide range of topics including innate immunity and inflammation, development, immune receptors, signaling and apoptosis, antigen presentation, gene regulation and recombination, cellular and systemic immunity, vaccines, immune tolerance, autoimmunity, tumor immunology, and microbial immunopathology. In addition to publishing significant original research, Nature Immunology also includes comments, News and Views, research highlights, matters arising from readers, and reviews of the literature. The journal serves as a major conduit of top-quality information for the immunology community.