Yin Bo, Ding Jianyi, Liu Jie, Hu Haoran, Zhu Yashi, Yang Meiqin, Zhou Huijuan, Huang Baoyou, Huang Tiefeng, Li Mengjie, He Yinyan, Li Ang, Han Lingfei
Department of Gynecology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
Department of Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Adv Sci (Weinh). 2025 May 28:e04436. doi: 10.1002/advs.202504436.
Exosomes shape the tumor microenvironment (TME) by modulating tumor-associated macrophages (TAMs) and promoting ovarian cancer (OC) progression. This study reveals that exosomal CKLF Like MARVEL Transmembrane Domain Containing 4 (CMTM4) enhances OC malignancy and orchestrates immune evasion. Excessive macrophage infiltration in the TME, particularly in the presence of CMTM4, is strongly associated with poor prognosis. Within the TME, exosomal CMTM4 is actively internalized by macrophages, promoting M2 polarization and subsequently initiating immunosuppressive signaling. Exosomal CMTM4 activates the NF-κB pathway in TAMs, suppressing immune function through enhanced secretion of cytokines, including TGF-β1 and CXCL12, while simultaneously upregulating intercellular adhesion molecule-1 (ICAM1) expression to further promote M2 polarization and facilitate cancer metastasis. Depletion of CMTM4 increases sensitivity to anti-PD-1 therapy by reversing immunosuppression. Notably, eltrombopag is identified as a CMTM4 inhibitor that attenuates OC progression in vivo and modulates the tumor immune microenvironment, synergizing with PD-1 blockade immunotherapy to enhance therapeutic efficacy. The exosomal CMTM4-ICAM1-CD206 axis exacerbates disease risk in patients with OC. Collectively, the study highlights the critical role of tumor-derived exosomal CMTM4 in immune suppression, emphasizing its potential as both a prognostic biomarker and a therapeutic target in OC immunotherapy.
外泌体通过调节肿瘤相关巨噬细胞（TAM）并促进卵巢癌（OC）进展来塑造肿瘤微环境（TME）。本研究表明，外泌体含CKLF样MARVEL跨膜结构域4（CMTM4）可增强OC的恶性程度并协调免疫逃逸。TME中巨噬细胞过度浸润，尤其是在存在CMTM4的情况下，与预后不良密切相关。在TME内，外泌体CMTM4被巨噬细胞主动内化，促进M2极化并随后启动免疫抑制信号传导。外泌体CMTM4激活TAM中的NF-κB途径，通过增强包括TGF-β1和CXCL12在内的细胞因子分泌来抑制免疫功能，同时上调细胞间粘附分子-1（ICAM1）表达以进一步促进M2极化并促进癌症转移。CMTM4的缺失通过逆转免疫抑制增加对抗PD-1治疗的敏感性。值得注意的是，艾曲泊帕被鉴定为一种CMTM4抑制剂，可在体内减弱OC进展并调节肿瘤免疫微环境，与PD-1阻断免疫疗法协同作用以增强治疗效果。外泌体CMTM4-ICAM1-CD206轴加剧了OC患者的疾病风险。总的来说，该研究突出了肿瘤来源的外泌体CMTM4在免疫抑制中的关键作用，强调了其作为OC免疫治疗中预后生物标志物和治疗靶点的潜力。
