Li Qinke, Zhang Siying, Wang Min, Yi Qiang, Xu Hang, Wang Jinlong, Yang Zhu
Department of Immunology, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, China.
Department of Gynecology and Obstetrics, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Oncogene. 2025 Aug 12. doi: 10.1038/s41388-025-03522-w.
The tumor microenvironment (TME) coordinates cancer progression through complex transcriptional networks, but the molecular mechanisms controlling immune evasion in ovarian cancer remain elusive. Here, by integrating immune dysfunction characteristics across multiple clinical cohorts and single-cell transcriptomics, we identified MAFB as a major regulator of ovarian cancer progression. MAFB expression exhibited stage-dependent elevation and was associated with immune checkpoint characteristics. Mechanistically, MAFB competitively binds to the core component WTAP of the m6A methyltransferase complex, thereby antagonizing the degradation of target gene mRNAs (WNT5A, CD55). This atypical regulatory axis leads to persistent expression of the target genes, further coordinating tumor cell invasiveness and immune landscape remodeling through cytoskeletal protein reorganization, M2 macrophage polarization, and regulatory T cell infiltration. Correlative analyses in patient cohorts and therapeutic effects in preclinical models support the clinical relevance of this pathway. Our findings uncover a novel mechanism by which MAFB promotes ovarian cancer progression through cytoskeletal remodeling and immune suppression, connecting transcriptional regulation with epitranscriptomic modifications, and identify the MAFB-WTAP-CD55 axis as a potential therapeutic target in ovarian cancer.
肿瘤微环境（TME）通过复杂的转录网络协调癌症进展，但卵巢癌中控制免疫逃逸的分子机制仍不清楚。在此，通过整合多个临床队列的免疫功能障碍特征和单细胞转录组学，我们确定MAFB是卵巢癌进展的主要调节因子。MAFB表达呈现出阶段依赖性升高，并与免疫检查点特征相关。从机制上讲，MAFB与m6A甲基转移酶复合体的核心成分WTAP竞争性结合，从而拮抗靶基因mRNA（WNT5A、CD55）的降解。这种非典型调节轴导致靶基因持续表达，通过细胞骨架蛋白重组、M2巨噬细胞极化和调节性T细胞浸润进一步协调肿瘤细胞侵袭性和免疫格局重塑。患者队列中的相关性分析和临床前模型中的治疗效果支持了该途径的临床相关性。我们的研究结果揭示了一种新机制，即MAFB通过细胞骨架重塑和免疫抑制促进卵巢癌进展，将转录调控与表观转录组修饰联系起来，并确定MAFB-WTAP-CD55轴为卵巢癌的潜在治疗靶点。
