Exosomal CMTM4 Induces Immunosuppressive Macrophages to Promote Ovarian Cancer Progression and Attenuate Anti‐PD‐1 Immunotherapy
Abstract 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...
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Wiley
2025-08-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202504436 |
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| author | Bo Yin Jianyi Ding Jie Liu Haoran Hu Yashi Zhu Meiqin Yang Huijuan Zhou Baoyou Huang Tiefeng Huang Mengjie Li Yinyan He Ang Li Lingfei Han |
| author_facet | Bo Yin Jianyi Ding Jie Liu Haoran Hu Yashi Zhu Meiqin Yang Huijuan Zhou Baoyou Huang Tiefeng Huang Mengjie Li Yinyan He Ang Li Lingfei Han |
| author_sort | Bo Yin |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-4f1abc0f2d314b8d98f08bc80bcab69d |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-4f1abc0f2d314b8d98f08bc80bcab69d2025-08-20T11:56:10ZengWileyAdvanced Science2198-38442025-08-011230n/an/a10.1002/advs.202504436Exosomal CMTM4 Induces Immunosuppressive Macrophages to Promote Ovarian Cancer Progression and Attenuate Anti‐PD‐1 ImmunotherapyBo Yin0Jianyi Ding1Jie Liu2Haoran Hu3Yashi Zhu4Meiqin Yang5Huijuan Zhou6Baoyou Huang7Tiefeng Huang8Mengjie Li9Yinyan He10Ang Li11Lingfei Han12Department 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 ChinaDepartment 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 ChinaDepartment of Gynecology Shanghai Tenth People's Hospital Tongji University School of Medicine Shanghai ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment of Gynecology Shanghai Tenth People's Hospital Tongji University School of Medicine Shanghai ChinaDepartment of Gynecology Shanghai Tenth People's Hospital Tongji University School of Medicine Shanghai ChinaDepartment of Gynecology Shanghai Tenth People's Hospital Tongji University School of Medicine Shanghai ChinaSchool of life science and technology Tongji University Shanghai ChinaDepartment 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 ChinaAbstract 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.https://doi.org/10.1002/advs.202504436CMTM4exosomal CMTM4macrophage polarizationovarian cancertumor‐associated macrophages |
| spellingShingle | Bo Yin Jianyi Ding Jie Liu Haoran Hu Yashi Zhu Meiqin Yang Huijuan Zhou Baoyou Huang Tiefeng Huang Mengjie Li Yinyan He Ang Li Lingfei Han Exosomal CMTM4 Induces Immunosuppressive Macrophages to Promote Ovarian Cancer Progression and Attenuate Anti‐PD‐1 Immunotherapy Advanced Science CMTM4 exosomal CMTM4 macrophage polarization ovarian cancer tumor‐associated macrophages |
| title | Exosomal CMTM4 Induces Immunosuppressive Macrophages to Promote Ovarian Cancer Progression and Attenuate Anti‐PD‐1 Immunotherapy |
| title_full | Exosomal CMTM4 Induces Immunosuppressive Macrophages to Promote Ovarian Cancer Progression and Attenuate Anti‐PD‐1 Immunotherapy |
| title_fullStr | Exosomal CMTM4 Induces Immunosuppressive Macrophages to Promote Ovarian Cancer Progression and Attenuate Anti‐PD‐1 Immunotherapy |
| title_full_unstemmed | Exosomal CMTM4 Induces Immunosuppressive Macrophages to Promote Ovarian Cancer Progression and Attenuate Anti‐PD‐1 Immunotherapy |
| title_short | Exosomal CMTM4 Induces Immunosuppressive Macrophages to Promote Ovarian Cancer Progression and Attenuate Anti‐PD‐1 Immunotherapy |
| title_sort | exosomal cmtm4 induces immunosuppressive macrophages to promote ovarian cancer progression and attenuate anti pd 1 immunotherapy |
| topic | CMTM4 exosomal CMTM4 macrophage polarization ovarian cancer tumor‐associated macrophages |
| url | https://doi.org/10.1002/advs.202504436 |
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