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A Copper-Manganese Based Nanocomposite Induces Cuproptosis and Potentiates Anti-Tumor Immune Responses

Luoyingzi Xie,Jie Gong,Zhiqiang He,Weinan Zhang,Haoyu Wang,Shitao Wu,Xianxing Wang,Pijiang Sun,Lei Cai,Zhongjun Wu,Huaizhi Wang

Cancer is one of the most important challenges worldwide with an increasing incidence. However, most of patients with malignant cancer receiving traditional therapies have tumor recurrence and short-term 5-year survival. Herein, a novel Cu 2 O-MnO@PEG (CMP) nanomaterial is developed to treat tumors. CMP directly mediates cuproptosis in tumor cells. Meanwhile, CMP potentiates anti-tumor immune responses in the tumor microenvironment (TME) to induce tumor regression. CMP improves the tumor antigen processing and presentation of dendritic cells and tumor-associated macrophages, and further promotes CD8 + T cell responses, especially for cytotoxic CD8 + T cells and transitory exhausted CD8 + T cells. Additionally, CMP downregulates the proportion of Treg cells and CTLA-4 expression on Treg cells. Notably, CMP induces systemic immune responses against distant tumors and long-term immune memory. Furthermore, CMP synergized with PD-L1 mAb promotes tumor inhibition and sustains the anti-tumor efficacy post PD-L1 mAb treatment. Collectively, this strategy has the clinically therapeutic potential for tumors by facilitating cuproptosis in tumor cells and anti-tumor immune responses.