Cascade loop of ferroptosis induction and immunotherapy based on metal‐phenolic networks for combined therapy of colorectal cancer

Cancer immunotherapy is the most promising method for tumor therapy, while ferroptosis could activate the immunogenicity of cancer and strengthen the cellular immune response. However, limited by the complex tumor microenvironment, the abundant glutathione (GSH) and low reactive oxygen species (ROS) seriously weaken ferroptosis and the immune response. Herein, the authors report photothermal metal-phenolic networks (MPNs) supplied with buthionine sulfoximine (BSO) by reducing levels of GSH and then trapping the tumor cells in the ferroptosis and immunotherapy cascade loop to eliminate colorectal cancer (CRC). The MPNs coated with the model antigen ovalbumin can accumulate at the tumor site, mediate immunogenic cell death (ICD) under NIR irradiation, and initiate tumoricidal immunity. Then the activated CD8+ T cells would release IFN-γ to inhibit GPX4 and promote the immunogenic ferroptosis induced by Fe3+ and BSO. Finally, the tumor cells at intertumoral and intratumoral levels would be involved in the ferroptosis-dominated cancer-immunity circle for CRC eradication, resulting in outstanding therapeutic outcomes in both primary and distant tumor models. Overall, this strategy employs a photothermal nanoplatform to rapidly stimulate ICD and restrain the oxidation defense system, which provides a promising approach to significantly amplify the "cascade loop" of ferroptosis induction and immunotherapy for treatment of CRC.