Metal-Phenolic Vehicles Potentiate Cycle-Cascade Activation of Pyroptosis and cGAS-STING Pathway for Tumor Immunotherapy

Abstract

The treatment of triple-negative breast cancer (TNBC) faces challenges due to its limited immune response and weak tumor immunogenicity. A collaborative strategy involves combining the activation of pyroptosis and the stimulator of interferon genes (STING) pathway to enhance tumor immunogenicity and fortify the antitumor immune response, which may improve therapeutic outcomes in TNBC. In this study, we report the fabrication of a zinc-phenolic nanocapsule (RMP@Cap), which is loaded with mitoxantrone (MTO) and anti-PD-L1 antibodies (aPD-L1) and coated with erythrocyte membrane, for TNBC immunotherapy. The delivery of RMP@Cap can induce tumor cell pyroptosis and, therefore, trigger the release of mitochondrial DNA, which further combines with zinc agonists to intensify STING activation, resulting in a cascade amplification of the therapeutic effect on tumors. Additionally, the incorporation of aPD-L1 into the zinc-phenolic nanocapsule relieves the inhibitory effect of tumor cells on recruited cytotoxic T cells, thereby improving the tumor-killing capacity. Furthermore, the incorporation of a camouflaged erythrocyte membrane coating enables nanocapsules to achieve prolonged in vivo circulation, resulting in improved tumor accumulation for effective antitumor therapy. This study demonstrates a synergistic therapeutic modality involving pyroptosis, coupled with the simultaneous activation and cyclic amplification of the STING pathway in immunotherapy.