Tumors evade attacks from the immune system through various mechanisms. Here, we identify a component of tumor immune evasion mediated by YTH domain–containing family protein 2 (YTHDF2), a reader protein that usually destabilizes m 6 A-modified mRNA. Loss of tumoral YTHDF2 inhibits tumor growth and prolongs survival in immunocompetent tumor models. Mechanistically, tumoral YTHDF2 deficiency promotes the recruitment of macrophages via CX3CL1 and enhances mitochondrial respiration of CD8 + T cells by impairing tumor glycolysis metabolism. Tumoral YTHDF2 deficiency promotes inflammatory macrophage polarization and antigen presentation in the presence of IFN-γ. In addition, IFN-γ induces autophagic degradation of tumoral YTHDF2, thereby sensitizing tumor cells to CD8 + T cell–mediated cytotoxicity. Last, we identified a small molecule compound that preferentially induces YTHDF2 degradation, which shows a potent antitumor effect alone but a better effect when combined with anti–PD-L1 or anti–PD-1 antibodies. Collectively, YTHDF2 appears to be a tumor-intrinsic regulator that orchestrates immune evasion, representing a promising target for enhancing cancer immunotherapy.

中文翻译：

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m 6 A 阅读器 YTHDF2 在调节免疫逃避中的肿瘤内在作用


肿瘤通过多种机制逃避免疫系统的攻击。在这里，我们鉴定了由包含 YTH 结构域的家族蛋白 2 (YTHDF2) 介导的肿瘤免疫逃避的一个组成部分，YTHDF2 是一种读取蛋白，通常会破坏 m 6 A 修饰的 mRNA 的稳定性。肿瘤 YTHDF2 的缺失会抑制肿瘤生长并延长免疫活性肿瘤模型的生存期。从机制上讲，肿瘤 YTHDF2 缺陷可通过 CX3CL1 促进巨噬细胞的募集，并通过损害肿瘤糖酵解代谢来增强 CD8 + T 细胞的线粒体呼吸。肿瘤 YTHDF2 缺陷会在 IFN-γ 存在的情况下促进炎症巨噬细胞极化和抗原呈递。此外，IFN-γ诱导肿瘤YTHDF2的自噬降解，从而使肿瘤细胞对CD8+T细胞介导的细胞毒性敏感。最后，我们鉴定了一种优先诱导 YTHDF2 降解的小分子化合物，该化合物单独显示出有效的抗肿瘤作用，但与抗 PD-L1 或抗 PD-1 抗体联合使用时效果更好。总的来说，YTHDF2 似乎是一种肿瘤内在调节因子，可以协调免疫逃避，代表了增强癌症免疫治疗的一个有希望的靶标。