Metal–Phenolic Networks-Based Nanozyme Reprograms Tumor Metabolism and Immunosuppressive Microenvironment to Enhance Ferroptosis and Potentiate Cancer Immunotherapy

The resistance of tumor cells to ferroptosis and their evasion from immune surveillance pose significant challenges in cancer treatment. Herein, a multifunctional nanozyme (PA-MPGD) is constructed via the assembly of metal-phenolic networks and concurrently loaded with glucose oxidase (GOx), piceatannol, and dioscin. The encapsulated GOx facilitates glucose consumption and hydrogen peroxide generation to hamper the pentose phosphate pathway of glucose and slash the biosynthesis of glutathione. Simultaneously, the nanozyme exhibiting catalase, peroxidase, and glutathione peroxidase-mimicking activities promotes oxygen formation, hydroxyl radical production, and glutathione depletion, thereby disintegrating the antioxidant capacity of tumor cells and inducing notable ferroptosis. Furthermore, in addition to the immunogenic cell death triggered by enhanced ferroptosis, repolarization of M2 tumor-associated macrophages into the M1 phenotype and inhibition of prostaglandin E2 synthesis were achieved by dioscin and piceatannol, respectively. They collectively contribute to reversing tumor microenvironment immunosuppression and eliciting a potent cellular immune response, which not only enables the elimination of primary tumors but also effectively resists lung metastasis of tumor cells. Overall, this study proposes a reliable strategy for enhancing ferroptosis and antitumor immunity to fulfill a more effective tumor therapy.