近日，美国加州大学余建华小组的论文发现了YTHDF2缺失可增强Th9编程和CAR-Th9细胞抗肿瘤效果。2025年8月18日出版的《自然—免疫学》发表了这项成果。

在这里，该课题组发现YTHDF2是一种重要的m⁶A解读蛋白，已知可以破坏m⁶A修饰的mRNA的稳定性，并负向调节Th9细胞的分化。消融小鼠和人原生CD4⁺ T细胞中的Ythdf2分别通过稳定白细胞介素-4 （IL-4）和转化生长因子β (TGF-β)信号下的Gata3和Smad3 mRNA来促进Th9分化。缺乏Ythdf2的Th9细胞产生IL-9和IL-21的量增加，导致CD8⁺ T细胞和自然杀伤（NK）细胞对肿瘤的浸润和细胞毒性增加，从而与野生型Th9细胞相比，抗肿瘤活性提高。

此外，CAR-Th9细胞中YTHDF2的缺失增强了其免疫激活，降低了其终末分化，增强了其抗肿瘤功效。因此，靶向YTHDF2是增强Th9和CAR-Th9细胞为基础的癌症免疫治疗的一种有希望的策略。

研究人员表示，CD4⁺ T细胞分化为各种亚群，包括辅助性T细胞1 （Th1）、Th2、Th9、Th17和调节性T细胞（T_reg），它们对免疫反应和癌症免疫治疗至关重要。然而，RNA N⁶ -甲基腺苷（m⁶A）修饰在这种分化中的作用尚不清楚。

附：英文原文

Title: Loss of YTHDF2 enhances Th9 programming and CAR-Th9 cell antitumor efficacy

Author: Xiao, Sai, Duan, Songqi, Hong, Yaqun, Zhang, Jianying, Ma, Shoubao, Caligiuri, Michael A., Yu, Jianhua

Issue&Volume: 2025-08-18

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.

DOI: 10.1038/s41590-025-02235-2

Source: https://www.nature.com/articles/s41590-025-02235-2