Amplifying STING activation and immunogenic cell death by metal-polyphenol coordinated nanomedicines for enhanced cancer immunotherapy

Abstract

Ferroptosis in combination with immune therapy emerges as a promising approach for cancer therapy. Herein, dual-responsive metal-polyphenol coordinated nanomedicines were developed for pH/glutathione (GSH)-responsive synergistic ferroptosis and immunotherapy. Our innovative strategy involves the development of a manganese-polyphenol coordinated nanostructure, leveraging the biocompatibility of bovine serum albumin (BSA) as a template to encapsulate the anticancer drug sorafenib. The tumor microenvironment (pH/GSH) prompts the disassembly of MnO₂ and epigallocatechin gallate (EGCG), thereby releases the anticancer payload. Concurrently, MnO₂ acts to deplete intracellular GSH, which in turn suppresses glutathione peroxidase activity, leading to an accumulation of lipid peroxides with cell ferroptosis. Additionally, the release of Mn²⁺ ions bolster the cyclic guanosine monophosphlic acid (GMP)-adenosine monophosphlic acid (AMP) synthase-stimulator of interferon gene (cGAS-STING) pathway, which, in conjunction with the immunogenic cell death (ICD) effect induced by tumor cell apoptosis, significantly promotes dendritic cell (DC) maturation and enhances the presentation of tumor antigens. This successively ignites a robust innate and adaptive immune response. Both in vitro and in vivo experiments have demonstrated that the concurrent administration of ferroptosis-inducing and immune-stimulating therapies can significantly inhibit tumor growth.