We aimed to restore MHC-I expression on the surface of solid tumors including breast cancer and melanoma cells to regain sensitivity to immunotherapy and suppress metastatic progression. We screened a natural compound library and identified macbecin II as a reagent that upregulates MHC-I expression and induces antigen-dependent cell death in pre-invasive and invasive breast cancer models. Furthermore, we employed active immunotherapy using engineered small extracellular vesicles from dendritic cells (DCs) as a tumor vaccine (IL2-ep13nsEV) in combination with macbecin II for personalized breast cancer treatment. We found that macbecin II induced MHC-I-dependent antigen presentation and that IL2-ep13nsEV synergized with macbecin II inducing cell death, reducing metastasis, and boosting immune cell infiltration. In addition, macbecin II potentiated the effects of anti-PD-1 immunotherapy in suppressing tumor growth and metastasis. Mechanistically, macbecin II upregulated MHC-I expression post-translationally by rescuing it from lysosomal degradation. Our findings revealed a strong efficacy of macbecin II in regulating MHC-I expression and following antigen-dependent cell death. Therefore, combining active immunotherapies and macbecin II represents an effective strategy to prevent growth and progression of solid tumors including breast cancer and melanoma.
MHC-I upregulation by macbecin II in the solid tumors potentiates the effect of active immunotherapy.
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作者:Deshpande Ravindra Pramod, Wu Kerui, Wu Shih-Ying, Tyagi Abhishek, Smith Eleanor C, Kim Jee-Won, Watabe Kounosuke
期刊: | EMBO Molecular Medicine | 影响因子: | 8.300 |
时间: | 2025 | 起止号: | 2025 Apr;17(4):797-822 |
doi: | 10.1038/s44321-025-00213-7 |
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