Abstract

Immune evasion driven by aberrant PD-L1 expression poses a significant challenge to the efficacy of cancer immunotherapy. Although Mitofusin-2 (MFN2) is recognized for its role in tumor suppression, its specific contribution to the regulation of immune escape remains poorly understood. Here, we integrated analyses of public datasets, clinical specimens, and mechanistic experiments in multiple cancer cell lines, immunocompetent mouse models, and patient-derived organoids. A combination of molecular assays and single-cell transcriptomic reanalysis was employed to elucidate how MFN2 influences tumor immune escape. MFN2 expression was markedly reduced in various cancers and inversely correlated with PD-L1 levels and immunosuppressive gene signatures. Functional assays demonstrated that MFN2 suppresses PD-L1 transcription by limiting EGFR-dependent activation and nuclear translocation of STAT3. Loss of MFN2 enhanced PD-L1 expression, impaired CD8 + T-cell cytotoxicity, and accelerated tumor growth in immunocompetent mice. Conversely, restoration of MFN2 or pharmacological inhibition of STAT3 decreased PD-L1 expression and reactivated antitumor immunity. Our findings identify MFN2 as a critical suppressor of tumor immune evasion through the EGFR/STAT3–PD-L1 signaling pathway. Targeting this axis may offer a novel strategy to enhance the efficacy of PD-1/PD-L1–based immunotherapy.