卵巢癌（OC）通常通过宿主免疫细胞的功能变化形成免疫抑制微环境。 m6A 水平失调通过内在致癌途径与癌症进展相关。但m6A在抗肿瘤免疫过程中调节宿主免疫细胞功能的作用还需要综合分析。本研究旨在探讨甲基转移酶复合物的催化亚基 METTL3 在调节宿主免疫细胞对 OC 反应中的作用。在本研究中，使用 Cre-LoxP 培育骨髓特异性 Mettl3 基因敲除 (Mettl3-cKO) 小鼠系统。腹腔注射ID8细胞作为同基因OC模型。此外，通过流式细胞术和单细胞测序分析了免疫细胞群的组成。此外，使用 ELISA 评估趋化因子和细胞因子的分泌。最后，通过ELISA和免疫印迹明确了METTL3在调节与ID8细胞共培养的骨髓源性巨噬细胞中IL-1β分泌和炎性小体激活中的作用。结果表明，Mettl3-cKO小鼠中OC细胞生长增强。此外，在 OC 进展过程中观察到巨噬细胞极化从 M1 减少转变为 M2 增加。此外，骨髓谱系细胞中Mettl3的消耗增加了腹腔灌洗液中CCL2和CXCL2的分泌。有趣的是，Mettl3 缺陷增强了 ID8 活细胞诱导的 IL-1β 分泌，与炎性体激活和细胞死亡无关。因此，荷瘤小鼠的 OC 细胞会引发轻微的炎症反应，并分泌低至中度的促炎细胞因子和趋化因子。这项研究为 METTL3 介导的 m6A 甲基化提供了新的见解，该甲基化调节宿主针对 OC 的免疫反应。 © 2023。作者。

Ovarian cancer (OC) typically develops an immunosuppressive microenvironment by funtional changes of host immune cells. Dysregulated m6A level is associated with cancer progression via the intrinsic oncogenic pathways. However, the role of m6A in regulating host immune cell function during anti-tumor immunity needs comprehensive analysis. This study aimed to investigate the role of METTL3, a catalytic subunit of the methyltransferase complex, in regulating host immune cell response against OC.In this study, myeloid-specific Mettl3 gene knockout (Mettl3-cKO) mice were bred using the Cre-LoxP system. Intraperitoneally injection of ID8 cells was used as a syngeneic OC model. Furthermore, the compositions of immune cell populations were analyzed by flow cytometry and single-cell sequencing. Moreover, chemokines and cytokines secretion were assessed using ELISA. Lastly, the role of METTL3 in regulating IL-1β secretion and inflammasome activation in bone marrow-derived macrophages cocultured with ID8 cells was specified by ELISA and immunoblotting.It was revealed that OC cell growth was enhanced in Mettl3-cKO mice. Furthermore, a shift of decreased M1 to increased M2 macrophage polarization was observed during OC progression. Moreover, Mettl3 depletion in myeloid lineage cells increased secretion of CCL2 and CXCL2 in peritoneal lavage fluild. Interestingly, Mettl3 deficiency enhanced IL-1β secretion induced by viable ID8 cells independent of inflammasome activation and cell death. Therefore, OC cells in tumor-bearing mice trigger a slight inflammatory response with a low-to-moderate secretion of pro-inflammatory cytokines and chemokines.This study provides new insights into METTL3-mediated m6A methylation, which regulates host immune response against OC.© 2023. The Author(s).