Natural killer (NK) cells exert critical roles in anti-tumor immunity but how their functions are regulated by epitranscriptional modification (e.g., N⁶-methyladenosine (m⁶A) methylation) is unclear. Here we report decreased expression of the m⁶A “writer” METTL3 in tumor-infiltrating NK cells, and a positive correlation between protein expression levels of METTL3 and effector molecules in NK cells. Deletion of Mettl3 in NK cells alters the homeostasis of NK cells and inhibits NK cell infiltration and function in the tumor microenvironment, leading to accelerated tumor development and shortened survival in mice. The gene encoding SHP-2 is m⁶A modified, and its protein expression is decreased in METTL3-deficient NK cells. Reduced SHP-2 activity renders NK cells hyporesponsive to IL-15, which is associated with suppressed activation of the AKT and MAPK signaling pathway in METTL3-deficient NK cells. These findings show that m⁶A methylation safeguards the homeostasis and tumor immunosurveillance function of NK cells.

自然杀伤 (NK) 细胞在抗肿瘤免疫中发挥关键作用，但它们的功能如何通过外转录修饰（例如，N ⁶ -甲基腺苷(m ⁶ A) 甲基化）进行调节尚不清楚。在这里，我们报告了肿瘤浸润性 NK 细胞中m ⁶ A“写入器”METTL3 的表达降低，以及 METTL3 的蛋白质表达水平与 NK 细胞中的效应分子之间的正相关。NK 细胞中Mettl3 的缺失会改变 NK 细胞的稳态并抑制 NK 细胞在肿瘤微环境中的浸润和功能，导致肿瘤加速发展并缩短小鼠的存活期。编码SHP-2的基因是m ⁶A 修饰，其蛋白质表达在 METTL3 缺陷的 NK 细胞中降低。SHP-2 活性降低使 NK 细胞对 IL-15 反应迟钝，这与 METTL3 缺陷 NK 细胞中 AKT 和 MAPK 信号通路的抑制激活有关。这些发现表明，m ⁶ A 甲基化保护了 NK 细胞的稳态和肿瘤免疫监视功能。