Zhenzhen Chen, Zhe Feng, Siyuan Wang, Jingjing Zhang
Abstract Chemo‐metalloimmunotherapy is emerging as a promising strategy for cancer treatment by integrating chemotherapy‐induced immunogenicity with metal ion‐mediated immune activation. However, its efficacy is hampered by chemoresistance and immune escape driven by PD‐L1 upregulation. Here, a multifunctional manganese‐based metal‐organic framework nanoplatform (Mn‐CDDP‐dBET6@CM) is reported that integrates metalloimmunotherapy, chemotherapy, and Proteolysis‐targeting chimera (PROTAC) ‐mediated epigenetic modulation for enhanced cancer treatment. This system co‐delivers Mn 2+ to activate the stimulator of interferon genes (STING) pathway, cisplatin (CDDP) to induce nucleus DNA damage, and the bromodomain‐containing protein 4 (BRD4) ‐targeting PROTAC dBET6 to promote mitochondrial DNA release and suppress PD‐L1‐mediated immune evasion. Coated with tumor cell membranes for homologous targeting and immune evasion, Mn‐CDDP‐dBET6@CM effectively induces cellular senescence, robust innate and adaptive immune activation, and tumor microenvironment remodeling. In vitro and in vivo studies demonstrate potent tumor growth inhibition, enhance dendritic cell maturation, and increase cytotoxic T cell infiltration. This nanoplatform offers a promising strategy to overcome chemoresistance and immunosuppression, providing a versatile approach for next‐generation chemo‐metalloimmunotherapy.