MHC-I upregulation by macbecin II in the solid tumors potentiates the effect of active immunotherapy

MHC-I upregulation by macbecin II in the solid tumors potentiates the effect of active immunotherapy

Abstract 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 ex...

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Bibliographic Details
Main Authors: Ravindra Pramod Deshpande, Kerui Wu, Shih-Ying Wu, Abhishek Tyagi, Eleanor C Smith, Jee-Won Kim, Kounosuke Watabe
Format: Article
Language:English
Published: Springer Nature 2025-03-01
Series:EMBO Molecular Medicine
Subjects:
Active Immunotherapy
Anti-PD-1
Breast Cancer
Macbecin II
MHC-I
Online Access:https://doi.org/10.1038/s44321-025-00213-7
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Summary:Abstract 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.
ISSN:1757-4684

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