美国希望之城国家医疗中心Jianhua Yu和Michael A. Caligiuri共同合作，近期取得重要工作进展。他们研究发现YTHDF2通过CD8⁺ T细胞调控肿瘤相关巨噬细胞重编程并控制抗肿瘤免疫。相关论文2023年1月19日日在线发表于《自然—免疫学》杂志上。

据介绍，尽管肿瘤相关巨噬细胞（TAM）在形成肿瘤微环境（TME）中起着关键作用，但TAM影响TME并促进癌症进展的机制目前仍不清楚。

研究人员表明N⁶-甲基腺苷阅读器YTHDF2调节TAM的抗肿瘤功能。TAM中YTHDF2的缺陷通过将TAM重编程为抗肿瘤表型并增加其抗原交叉呈递能力来抑制肿瘤生长，从而增强CD8⁺ T细胞介导的抗肿瘤免疫。YTHDF2缺陷通过靶向干扰素-γ−STAT1信号促进TAM的重编程。TAM中YTHDF2的表达受白介素-10−STAT3信号调节。使用Toll样受体9激动剂偶联的小干扰RNA重编程TAM选择性靶向TAM中的YTHDF2，使其具有抗肿瘤表型，抑制肿瘤生长并增强PD-L1抗体治疗的效果。

总之，这一发现描述了YTHDF2在调节TAM中的作用，并表明抑制YTHDF2是增强癌症免疫治疗的有效途径。

附：英文原文

Title: YTHDF2 orchestrates tumor-associated macrophage reprogramming and controls antitumor immunity through CD8+ T cells

Author: Ma, Shoubao, Sun, Baofa, Duan, Songqi, Han, Jingjing, Barr, Tasha, Zhang, Jianying, Bissonnette, Marc B., Kortylewski, Marcin, He, Chuan, Chen, Jianjun, Caligiuri, Michael A., Yu, Jianhua

Issue&Volume: 2023-01-19

Abstract: 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-γSTAT1 signaling. The expression of YTHDF2 in TAMs was regulated by interleukin-10STAT3 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.

DOI: 10.1038/s41590-022-01398-6

Source: https://www.nature.com/articles/s41590-022-01398-6