Nanoparticles Synergize Ferroptosis and Cuproptosis to Potentiate Cancer Immunotherapy

• Published in: Advanced science Vol. 11; no. 23; pp. e2310309 - n/a
• Main Authors: Li, Youyou, Liu, Jing, Chen, Yimei, Weichselbaum, Ralph R., Lin, Wenbin
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01.06.2024; John Wiley and Sons Inc; Wiley
• Subjects: Animals; Cancer therapies; Cell death; Cell Line, Tumor; Copper; cuproptosis; Disease Models, Animal; Female; Ferroptosis; Ferroptosis - drug effects; Humans; Immunotherapy; Immunotherapy - methods; Lipid peroxidation; Lipids; Metabolism; Mice; Microemulsions; Nanoparticles; Piperazines; Proteins; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - immunology; Tumors; ferroptosis; nanoparticles; cuproptosis; immunotherapy
• DOI: 10.1002/advs.202310309
• ISSN: 2198-3844

The recent discovery of copper‐mediated and mitochondrion‐dependent cuproptosis has aroused strong interest in harnessing this novel mechanism of cell death for cancer therapy. Here the design of a core‐shell nanoparticle, CuP/Er, for the co‐delivery of copper (Cu) and erastin (Er) to cancer cells for synergistic cuproptosis and ferroptosis is reported. The anti‐Warburg effect of Er sensitizes tumor cells to Cu‐mediated cuproptosis, leading to irreparable mitochondrial damage by depleting glutathione and enhancing lipid peroxidation. CuP/Er induces strong immunogenic cell death, enhances antigen presentation, and upregulates programmed death‐ligand 1 expression. Consequently, CuP/Er promotes proliferation and infiltration of T cells, and when combined with immune checkpoint blockade, effectively reinvigorates T cells to mediate the regression of murine colon adenocarcinoma and triple‐negative breast cancer and prevent tumor metastasis. This study suggests a unique opportunity to synergize cuproptosis and ferroptosis with combination therapy nanoparticles to elicit strong antitumor effects and potentiate current cancer immunotherapies. This paper reports a core‐shell nanoparticle, CuP/Er, for the co‐delivery of copper (Cu) and erastin (Er) to cancer cells for synergistic cuproptosis and ferroptosis. CuP/Er induces strong immunogenic cell death, and when combined with immune checkpoint blockade, effectively reinvigorates T cells to mediate the regression of murine colon adenocarcinoma and triple‐negative breast cancer and prevent tumor metastasis.