Reshape Intracellular/Extracellular pH for Enhanced Nanocatalytic Ferroptosis and cGAS‐STING Activation Induced Immunotherapy

Nanometal-based therapies face challenges arising from the overexpression of proton efflux transporters in cancer cells, which acidifies the extracellular tumor microenvironment (TME) while preserving a relatively neutral intracellular pH, thereby compromising therapeutic efficacy and fostering an immunosuppressive TME. Here, we integrate the proton pump inhibitor pantoprazole (PTZ) with manganese ferrite nanoparticles (MFNs) within an acidity-responsive polymer for enhanced ferroptosis and cGAS-STING activation mediated immunotherapy. This assembly (PTZ/MFNAs) facilitates tumor accumulation through the enhanced permeability and retention effect while initially restricting the release of metal ions. Upon reaching the tumor site, PTZ release increases intracellular acidity, which further triggers assembly disintegration, accelerates the release of iron and manganese ions, and neutralizes the extracellular microenvironment to alleviate immunosuppression. The released manganese ions synergistically collaborate with iron ions to amplify reactive oxygen species (ROS) generation for ferroptosis while activating the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway, stimulating innate immunity. This potentiation of innate immunity, coupled with the reversal of TME immunosuppression, collectively and effectively inhibits tumor growth and metastasis. Therefore, the PTZ/MFNAs co-delivery system represents a promising pH-modulation strategy to enhance iron/manganese ions-mediated ferroptosis and cGAS-STING activation-induced immunotherapy.