Ferroptosis-induced immunomodulation with biometabolic MOF@COF nanovaccine for self-boosting anti-tumor immunotherapy

Ferroptosis, a regulated cell death pathway, presents a compelling approach for augmenting anti-tumor immunity, addressing challenges associated with immune escape and inadequate immunogenicity linked to apoptosis resistance. In this study, we introduce a biometabolic MOF@COF nanovaccine (NMCAH) designed to evoke self-amplifying anti-tumor responses through ferroptosis-mediated immune stimulation. The nanovaccine demonstrates the capacity to induce the generation of reactive oxygen species and deplete glutathione within tumors, initiating immunogenic ferroptosis. Simultaneously, it facilitates the polarization of macrophages toward the M1 phenotype and the maturation of CD8+ T cells. Upon priming, these immune cells autonomously amplify the response in a self-reinforcing manner. Notably, IFN-γ secretion by CD8+ T cells reinforces macrophage polarization and induces secondary ferroptosis via ACSL4 up-regulation. This intricately coordinated interplay between ferroptosis and adaptive immunity holds significant promise in overcoming the immunosuppressive tumor microenvironment. Our study establishes a versatile nanotherapeutic platform for advancing cancer immunotherapy by leveraging the immunogenic characteristics of regulated cell death.