N6-甲基腺苷(m6A)甲基化是mRNA中最丰富的化学转录后修饰，与肿瘤免疫反应调节有关。然而，m6A修饰在子宫内膜癌（EC）免疫反应中的作用尚不清楚。我们的研究调查了类甲基转移酶3（METTL3）在EC中的免疫学作用及其潜在的分子机制。我们使用子宫内膜组织微阵列队列研究了METTL3表达与CD8之间的相关性。接下来，我们在小鼠肿瘤模型和CD8+ T细胞-EC细胞共培养系统中，通过METTL3的过表达或减少来研究METTL3在EC免疫反应中的作用和机制。此外，使用RNA免疫沉淀（RIP）、甲基化RIP和RNA稳定性实验来研究METTL3在EC免疫监视中的功能机制。结果表明，EC患者METTL3水平下调，METTL3水平降低与EC患者预后不良相关。METTL3表达和CD8表达呈正相关。在EC细胞和CD8+ T细胞共培养系统中，METTL3的过表达抑制了EC细胞增殖、迁移并促进CD8+ T细胞增殖，而在体内，METTL3过表达增加了CD8+ T细胞比例并抑制了EC的进展；然而，METTL3基因缺失产生了相反的效果。核糖体NLR家族CARD域含蛋白5（NLRC5）被识别为METTL3介导的m6A修饰靶标。YTH结构域含蛋白家族2（YTHDF2）增加了NLRC5的降解。总的来说，METTL3、YTHDF2和NLRC5有望成为EC的诊断和预后生物标志物。METTL3通过促进NLRC5介导的免疫监视，通过YTHDF2依赖性机制抑制其降解，从而促进NLRC5的m6A修饰，减轻了EC的免疫逃逸，因此，METTL3/YTHDF2/NLRC5轴是EC免疫疗法的一个有前途的靶点。© 2023作者.

N6-methyladenosine (m6A) methylation is the most abundant chemical posttranscriptional modification of mRNA, and it is associated with the regulation of the immune response to tumors. However, the function of m6A modification in the immune response to endometrial cancer (EC) remains unknown. Our study investigated the immunological role of methyltransferase-like 3 (METTL3) in EC and the underlying molecular mechanism.We investigated the correlation between the expression of METTL3 and CD8 by using an endometrial tissue microarray cohort. Next, we investigated the role and mechanism of METTL3 in the immune response to EC using a mouse tumor model and a CD8+ T cell-EC cell coculture system after METTL3 overexpression or depletion. Additionally, RNA immunoprecipitation (RIP), methylated RIP, and RNA stability experiments were used to investigate the mechanism underlying the function of METTL3 in immunosurveillance of EC.METTL3 levels were downregulated in EC patients, low levels of METTL3 were correlated with poor prognosis in EC patients. There was a positive correlation between METTL3 expression and CD8 expression. Overexpression of METTL3 in the EC cell and CD8+ T cell coculture system inhibited EC cell proliferation, migration, and promoted CD8+ T-cell proliferation, and in vivo, METTL3 overexpression increased CD8+ T cell proportions and inhibited EC progression; however, genetic depletion of METTL3 exerted the opposite effects. NLR family CARD domain-containing 5 (NLRC5) was identified as a target of METTL3-mediated m6A modification. The degradation of NLRC5 was increased by YTH domain-containing family 2 (YTHDF2).Overall, METTL3, YTHDF2, and NLRC5 have potential to be the diagnostic and prognostic biomarkers for EC. METTL3 facilitated the m6A modifications of NLRC5 and inhibited its degradation through a YTHDF2-dependent mechanism in EC. Genetic overexpression of METTL3 attenuated the immune evasion of EC by promoting NLRC5-mediated immunosurveillance, suggesting that the METTL3/YTHDF2/NLRC5 axis is a promising target of immunotherapy in EC.© 2023. The Author(s).