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. 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.