ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1621816
This article is part of the Research TopicImmunological Aspects and Immunotherapy in Gynecologic CancersView all 15 articles
Oncogenic CMTM6 Drives M2a Macrophages Formation and Fuels Cervical Cancer Progression
Provisionally accepted
Lingfei Han1*
Bo Yin1
Chun Chen2,3
Baoyou Huang1Jianyi Ding1
Haoran Hu1Huijuan Zhou1Yashi Zhu1Tiefeng Huang1Xiang He4*
Yuan Lu3*- 1Tongji University, Shanghai, China
- 2Fudan university, Shanghai, China
- 3Fudan university, Shanghai City, China
- 4Shanghai University of Traditional Chinese Medicine, Shanghai, China
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CMTM6, a member of the CKLF like MARVEL transmembrane (CMTM) gene family, has emerged as a critical orchestrator of oncogenic processes, yet its specific role in cervical cancer (CC) remains insufficiently characterized. Mounting evidence implicates that CMTM6 in sculpting an immunosuppressive tumor microenvironment (TME). Here, we delineate how CMTM6-laden exosomes secreted by CC cells reprogramming macrophages and drive malignant progression. We analyzed the expression and functional role of CMTM6 in cervical cancer cells using in vitro biological assays and a mouse xenograft model. The impact of CMTM6 on macrophage polarization and its association with tumor progression were systematically evaluated. A comprehensive series of in vitro and in vivo experiments were conducted to assess the induction of M2a macrophage polarization and the activation of the mTOR signaling pathway, elucidating the immunomodulatory mechanisms mediated by CMTM6. Our findings demonstrate that exosomes secreted by CC cells encapsulate CMTM6, significantly promoting malignant progression and coordinating immune evasion. Excessive macrophage infiltration in the TME, especially in the presence of CMTM6, is strongly associated with unfavorable prognosis. Exosomal CMTM6 is actively internalized by macrophages, inducing M2a polarization and triggering immune-suppressive pathways. Moreover, exosomal CMTM6 activates the mTOR signaling pathway in tumor-associated macrophages, enhancing CCL2 secretion, which further promotes M2a polarization and accelerates tumor metastasis. Exosomal CMTM6 plays a crucial role in immune suppression in CC, with the CMTM6/CD206/CCL2 axis significantly increasing the risk for CC patients. Our findings underscore the potential of exosomal-CMTM6 as a prognostic biomarker and therapeutic target for CC immunotherapy.
Keywords: cervical cancer, CMTM6, Exosomal CMTM6, Macrophage polarization, M2A
Received: 02 May 2025; Accepted: 27 Jun 2025.
Copyright: © 2025 Han, Yin, Chen, Huang, Ding, Hu, Zhou, Zhu, Huang, He and Lu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Lingfei Han, Tongji University, Shanghai, China
Xiang He, Shanghai University of Traditional Chinese Medicine, Shanghai, China
Yuan Lu, Fudan university, Shanghai City, China
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