Targeting METTL3 reprograms the tumor microenvironment to improve cancer immunotherapy

• Published in: Cell chemical biology Vol. 31; no. 4; pp. 776 - 791.e7
• Main Authors: Yu, Haisheng, Liu, Jing, Bu, Xia, Ma, Zhiqiang, Yao, Yingmeng, Li, Jinfeng, Zhang, Tiantian, Song, Wenjing, Xiao, Xiangling, Sun, Yishuang, Xiong, Wenjun, Shi, Jie, Dai, Panpan, Xiang, Bolin, Duan, Hongtao, Yan, Xiaolong, Wu, Fei, Zhang, Wen Cai, Lin, Dandan, Hu, Hankun, Zhang, Haojian, Slack, Frank J., He, Housheng Hansen, Freeman, Gordon J., Wei, Wenyi, Zhang, Jinfang
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 18.04.2024
• Subjects: cancer immunotherapy; chemokines; METTL3; PD-L1; tumor microenvironment; PD-L1; tumor microenvironment; chemokines; METTL3; cancer immunotherapy
• ISSN: 2451-9456; 2451-9456
• DOI: 10.1016/j.chembiol.2023.09.001

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. [Display omitted] •METTL3 promotes the expression of CXCL1, CXCL5, and CCL20 via c-Myc in NSCLC•METTL3 mediates PD-L1 mRNA m6A modification, resulting in destabilizing PD-L1 in NSCLC•METTL3 inhibition improves anti-PD-1 therapy in syngeneic murine LLC tumor model•METTL3 deficiency enhances PD-1 blockade in KP and orthotopic mouse lung tumor models Yu et al. report inhibiting METTL3 reprograms an inflamed tumor microenvironment that renders anti-PD-1 therapy more effective in several preclinical mouse NSCLC tumor models, highlighting the combination of METTL3 inhibitor with PD-1/PD-L1 immune-checkpoint blockade as a promising therapeutic strategy for NSCLC patients.