尽管肿瘤相关巨噬细胞（TAMs）在塑造肿瘤微环境（TME）方面发挥关键作用，但TAMs影响TME并促进癌症进展的机制仍不清楚。我们展示了N6-甲基腺苷读取器YTHDF2调节TAMs的抗肿瘤功能。TAMs中的YTHDF2缺陷通过重新编程TAMs朝着抗肿瘤表型方向，增加它们的抗原十字交呈能力，从而增强CD8+ T细胞介导的抗肿瘤免疫力，抑制肿瘤生长。YTHDF2缺陷通过靶向干扰素-γ-STAT1信号促进TAMs的重新编程。TAMs中YTHDF2的表达受白细胞介素-10-STAT3信号的调节。使用Toll样受体9激动剂共轭的小干扰RNA选择性靶向TAMs中的YTHDF2重新编程TAMs朝着抗肿瘤表型方向，抑制肿瘤生长并增强PD-L1抗体疗法的疗效。总的来说，我们的发现描述了YTHDF2编排TAMs的作用，并建议通过YTHDF2抑制来提高癌症免疫治疗的效果。©2023年，由作者独家许可Springer Nature America，Inc.发行。

Despite tumor-associated macrophages (TAMs) playing a key role in shaping the tumor microenvironment (TME), the mechanisms by which TAMs influence the TME and contribute to cancer progression remain unclear. Here, we show that the N6-methyladenosine reader YTHDF2 regulates the antitumor functions of TAMs. YTHDF2 deficiency in TAMs suppressed tumor growth by reprogramming TAMs toward an antitumoral phenotype and increasing their antigen cross-presentation ability, which in turn enhanced CD8+ T cell-mediated antitumor immunity. YTHDF2 deficiency facilitated the reprogramming of TAMs by targeting interferon-γ-STAT1 signaling. The expression of YTHDF2 in TAMs was regulated by interleukin-10-STAT3 signaling. Selectively targeting YTHDF2 in TAMs using a Toll-like receptor 9 agonist-conjugated small interfering RNA reprogrammed TAMs toward an antitumoral phenotype, restrained tumor growth and enhanced the efficacy of PD-L1 antibody therapy. Collectively, our findings describe the role of YTHDF2 in orchestrating TAMs and suggest that YTHDF2 inhibition is an effective approach to enhance cancer immunotherapy.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.