Targeting METTL3 reprograms the tumor microenvironment to improve cancer immunotherapy

类型：

作者：Haisheng Yu, Jing Liu, Xia Bu, Zhiqiang Ma, Yingmeng Yao, Jinfeng Li, Tiantian Zhang, Wenjing Song, Xiangling Xiao, Yishuang Sun, Wenjun Xiong, Jie Shi, Panpan Dai, Bolin Xiang, Hongtao Duan, Xiaolong Yan, Fei Wu, Wen Cai Zhang, Dandan Lin, Hankun Hu, Haojian Zhang, Frank J. Slack, Housheng Hansen He, Gordon J. Freeman, Wenyi Wei, Jinfang Zhang
期刊：Cell Chemical Biology
阅读原文

The tumor microenvironment (TME) is a heterogeneous ecosystem containing cancer cells, immune cells, stromal cells, cytokines, and chemokines which together govern tumor progression and response to immunotherapies. Methyltransferase-like 3 (METTL3), a core catalytic subunit for RNA N6-methyladenosine (m6A) modification, plays a crucial role in regulating various physiological and pathological processes. Whether and how METTL3 regulates the TME and anti-tumor immunity in non-small-cell lung cancer (NSCLC) remain poorly understood. Here, we report that METTL3 elevates expression of pro-tumorigenic chemokines including CXCL1, CXCL5, and CCL20, and destabilizes PD-L1 mRNA in an m6A-dependent manner, thereby shaping a non-inflamed TME. Thus, inhibiting METTL3 reprograms a more inflamed TME that renders anti-PD-1 therapy more effective in several murine lung tumor models. Clinically, NSCLC patients who exhibit low-METTL3 expression have a better prognosis when receiving anti-PD-1 therapy. Collectively, our study highlights targeting METTL3 as a promising strategy to improve immunotherapy in NSCLC patients.