肿瘤微环境（TME）是一个异质生态系统，包含癌细胞、免疫细胞、基质细胞、细胞因子和趋化因子，它们共同控制肿瘤进展和对免疫疗法的反应。甲基转移酶样3（METTL3）是RNA N6-甲基腺苷（m6A）修饰的核心催化亚基，在调节各种生理和病理过程中发挥着至关重要的作用。 METTL3 是否以及如何调节非小细胞肺癌 (NSCLC) 中的 TME 和抗肿瘤免疫仍知之甚少。在此，我们报告 METTL3 提高促肿瘤趋化因子（包括 CXCL1、CXCL5 和 CCL20）的表达，并以 m6A 依赖性方式破坏 PD-L1 mRNA 的稳定性，从而形成非炎症的 TME。因此，抑制 METTL3 会重新编程更发炎的 TME，从而使抗 PD-1 疗法在几种小鼠肺肿瘤模型中更有效。临床上，METTL3低表达的NSCLC患者在接受抗PD-1治疗时预后较好。总的来说，我们的研究强调以 METTL3 为靶点作为改善 NSCLC 患者免疫治疗的一种有前景的策略。版权所有 © 2023 Elsevier Ltd。保留所有权利。

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.Copyright © 2023 Elsevier Ltd. All rights reserved.