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.

Introduction: 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).Methods: We investigated the expression and functional role of CMTM6 in CC 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 through a series of in vitro and in vivo experiments, focusing on the induction of M2a macrophage polarization and activation of the mTOR signaling pathway.Results: Our results demonstrate that exosomes secreted by CC cells encapsulate CMTM6, which is actively internalized by macrophages, inducing M2a polarization and triggering immunosuppressive pathways. Excessive macrophage infiltration in the TME, particularly in the presence of CMTM6, is strongly associated with unfavorable prognosis. Furthermore, exosomal CMTM6 activates the mTOR signaling pathway in tumor-associated macrophages, enhancing CCL2 secretion, which further promotes M2a polarization and accelerates tumor metastasis.Discussion: These findings highlight exosomal CMTM6 as a crucial driver of immune suppression in CC, with the CMTM6/CD206/CCL2 axis significantly increasing the risk for CC patients. Our study underscores the potential of exosomal CMTM6 as both a prognostic biomarker and a therapeutic target for CC immunotherapy.

Background: Immune tolerance in epithelial ovarian cancer (EOC) enables cancer cells to evade immune surveillance. Myeloid-derived suppressor cells (MDSCs), as crucial immunosuppressive regulators, shape the tumor microenvironment and contribute to resistance against immunotherapy. However, the regulatory mechanisms of MDSCs in ovarian cancer remain poorly understood. Methods: We examined the presence and distribution of MDSCs in peripheral blood and tumor tissues from EOC patients. Transcriptomic analysis was performed on ovarian cancer cells co-cultured with MDSCs. The role of Serum Amyloid A1 (SAA1) was investigated through in vitro functional assays, co-culture experiments, and in vivo mouse models. Results: MDSCs were enriched in both peripheral blood and tumor tissues of EOC patients. SAA1 was significantly upregulated in ovarian cancer cells after interaction with MDSCs and confirmed in tumor samples and cell lines. Functionally, SAA1 promoted cancer cell proliferation, migration, and invasion. It also recruited MDSCs via TLR2/4, induced the differentiation of granulocyte-monocyte progenitors (GMPs), and stimulated IL-1β secretion, which in turn enhanced SAA1 expression, forming a positive feedback loop. In vivo, SAA1 promoted tumor progression and ascites formation. Clinically, high levels of SAA1, IL-1β, and CD33⁺ MDSCs correlated with poor survival. Conclusion: This study uncovers a novel SAA1–IL-1β feedback loop that promotes immunosuppression and progression in ovarian cancer. These findings provide insight into tumor–immune interactions and suggest a potential biomarker and therapeutic target for EOC.

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.

Introduction: Ovarian cancer (OC) is the most lethal gynecological malignancy. A deeper insight into tumor microenvironment (TME) interactions is essential for developing novel therapeutic approaches. leukocyte immunoglobulin-like receptor B4 (LILRB4) is a receptor involved in multiple biological and pathological processes in hematological malignancies; however, its role in the progression of solid tumors remains largely unexplored. In particular, the function within the OC is still unclear. Methods: We systematically investigated the expression profile of LILRB4 in OC, along with its regulatory effects on OC cells, its role in immune cell modulation, and its potential as an immunotherapeutic target, using bioinformatics analyses, in vitro functional assays, and an in vivo orthotopic tumor model. Results: We found that LILRB4 is the most highly expressed member of the LILRB family in OC, with significantly higher expression in tumor tissues than in normal ovarian tissues, and its elevated expression was associated with poor patient survival. In vitro functional assays demonstrated that LILRB4 knockdown significantly inhibited OC cell proliferation, migration, and invasion, whereas overexpression of LILRB4 promoted these malignant phenotypes. Further analyses revealed that LILRB4 expression was positively correlated with the infiltration of tumor-associated macrophages in the TME and promoted macrophage polarization toward the immunosuppressive M2c phenotype. Mechanistically, in vitro experiments showed that LILRB4 promoted tumor cell secretion of CCL5, activated the NF-κB p65 signaling pathway, and enhanced M2c macrophage polarization, thereby promoting tumor progression and immune suppression. Finally, we demonstrated that downregulation of LILRB4 could enhance the sensitivity of OC to immunotherapy. Discussion: These findings identify LILRB4 as a key regulator of tumor progression and immune evasion in OC. High LILRB4 expression is associated with an immunosuppressive TME and poor response to immunotherapy, highlighting its potential as both a prognostic biomarker and a therapeutic target.

Background: Radiotherapy (RT) and immune checkpoint inhibitors (ICIs) have each transformed the treatment of malignant solid tumors (STs). Beyond direct tumor killing, RT remodels the tumor microenvironment (TME), promotes antigen release, and enhances immune activation. ICIs targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1) restore antitumor immunity by reversing T cell exhaustion. Increasing evidence indicates that RT can synergize with ICIs through mechanisms such as the abscopal effect, immunogenic cell death (ICD), and activation of the cyclic guanosine monophosphate–adenosine monophosphate (cGMP–AMP) synthase–stimulator of interferon genes (cGAS–STING) pathway. Methods: This review summarizes current radiobiological, immunological, and clinical evidence regarding the synergistic effects of RT and ICIs in malignant STs, with a focus on underlying mechanisms, recent clinical advances, and translational challenges. Results: RT can enhance tumor immunogenicity, promote immune priming, and reshape the TME to improve the efficacy of ICIs. Synergy between RT and ICIs is associated with ICD induction, cGAS‒STING activation, enhanced systemic antitumor immunity, and modulation of immune cell infiltration and checkpoint signaling. Clinical studies across multiple STs have shown encouraging efficacy and manageable safety, although outcomes vary according to tumor type, disease stage, radiation schedule, and patient selection. Conclusions: RT combined with ICIs is a promising therapeutic strategy for malignant STs. Further optimization of treatment regimens and biomarker-guided patient selection will be essential to maximize clinical benefit and enable more precise combination therapies.