A study of Targeting METTL3 reprograms the tumor microenvironment to improve cancer immunotherapy. Haisheng Yu et al.

The tumor microenvironment (TME) is a heterogenous 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) remains 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 better prognosis when receiving anti-PD-1 therapy. Collectively, our study highlights targeting METTL3 as a promising strategy to improve immunotherapy in NSCLC patients.

肿瘤微环境（TME）是一个由癌细胞、免疫细胞、基质细胞、细胞因子和趋化因子构成的异质生态系统，共同调控肿瘤的进展和对免疫疗法的反应。甲基转移酶样3（METTL3），作为RNA N6-甲基腺苷（m6A）修饰的核心催化亚基，在调节多种生理和病理过程中发挥着至关重要的作用。至于METTL3是否以及如何调节非小细胞肺癌（NSCLC）中的肿瘤微环境和抗肿瘤免疫，目前尚不明确。在本研究中，我们报道METTL3通过m6A依赖性方式上调促肿瘤趋化因子（如CXCL1、CXCL5和CCL20）的表达，并使PD-L1 mRNA不稳定，从而塑造出一个非炎症性的肿瘤微环境。因此，抑制METTL3可以重编程肿瘤微环境，使其更加炎症化，从而使抗PD-1疗法在多个小鼠肺肿瘤模型中更加有效。在临床方面，表现出低METTL3表达的NSCLC病人在接受抗PD-1治疗后预后较好。综上所述，本研究突出了靶向METTL3作为改善NSCLC病人免疫疗法前景广阔的策略。