Lactate‐Modulating Nanoreactors Facilitate Self‐Amplifying Pyroptosis and the cGAS‐STING Cascade for Potentiated Catalytic‐Immunotherapy

Abstract The strategic induction of pyroptosis, coupled with the targeted potentiation of cGAS‐STING activation, represents a promising immunostimulatory approach. Herein, an intelligent lactate‐depleting LOCoF 2 nanoreactor system is developed that orchestrated self‐amplifying pyroptosis induction and cGAS‐STING signaling potentiation for enhanced catalytic immunotherapy. This nanoplatform integrated cobalt fluoride (CoF 2 ) nanoparticles with lactate oxidase (LOx), endowing it with dual enzymatic capabilities. Therefore, the LOCoF 2 nanoreactor initially served as a pyroptosis activator, synergistically inducing pyroptosis in cancer cells by catalyzing the sequential generation of reactive oxygen species (ROS) while simultaneously inhibiting damage repair mechanisms. Subsequently, it functioned as an intelligent STING agonist to selectively detect pyroptosis‐released mitochondrial DNA (mtDNA) and augment the activation of the cGAS‐STING pathway. In vivo evaluations reveal that LOCoF 2 administration provoked robust antitumor immunity, with synergistic effects observed when combined with immune checkpoint inhibitors, leading to significant regression of both primary and distant lesions. Notably, the LOCoF 2 ‐lipiodol emulsion demonstrates exceptional therapeutic performance in a rat orthotopic hepatocellular carcinoma model when integrated with transcatheter arterial embolization (TAE) or transarterial chemoembolization (TACE) treatments. Therefore, the adverse factor lactate is ingeniously utilized to increase the activation of pyroptosis‐STING via a cascade reaction, ultimately achieving superior tumor control.