Lingfei Han

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.

Inhibiting CMTM4 reverses the immunosuppressive function of myeloid-derived suppressor cells and augments immunotherapy response in cervical cancer

CKLF (chemokine-like factor)-like MARVEL transmembrane domain-containing family member 4 (CMTM4), belonging to the CMTM family of transmembrane domain proteins, plays a significant role in the initiation, progression, and metastasis of cancer. Nevertheless, its involvement in tumor immunity remains elusive. In the present investigation, we observed an upregulation of CMTM4 expression in patients with cervical cancer (CC), which also serves as a prognostic indicator for patients with CC. In vitro experiments and therapeutic models have demonstrated that CMTM4 upregulates the expansion of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment via the CCL2 (C–C motif chemokine ligand 2)/CCR2 (C–C motif chemokine ligand 2) and IL-6 (interleukin-6)/GP130 (glycoprotein 130) axes. This process exerts immunosuppressive effects and promotes the occurrence and progression of CC. Mechanistically, CMTM4 interacts and stabilizes PHB2 (prohibitin 2) through post-translational modification, which further induces activation of the STING (stimulator of interferon genes)/TBK1 (TANK-binding kinase 1)/STAT6 (signal transducer and activator of transcription 6) pathway, facilitating the nuclear translocation of STAT6 which binds to the CCL2/IL-6 promoter, leading to the upregulation of CCL2/IL-6 transcription expression. Importantly, targeting CMTM4 with CMTM4-small interfering RNA enhanced the effectiveness of anti-programmed cell death protein 1 (anti-PD-1) therapy. Our study identifies CMTM4 as a crucial determinant guiding the homing of MDSCs to CC, thereby contributing to MDSCs-mediated immune suppression and tumor progression. The combination of CMTM4 inhibition and anti-PD-1 treatment shows promising antitumor efficacy against CC. These findings offer novel insights into the tumor microenvironment and have the potential to inform the development of innovative immunotherapy approaches for CC.