Metabolic modulation-driven self-reinforcing pyroptosis-STING nanoadjuvant for potentiated metalloimmunotherapy

Pyroptosis is a critical process that triggers inflammatory responses and mitochondrial DNA (mtDNA) release, thereby activating the cGAS-STING pathway. However, tumor metabolism, particularly glycolysis, often suppresses immune activation. To address this, we developed GOCoF₂, a self-amplifying pyroptosis-STING nanoadjuvant that integrates glucose oxidase (GOx) with cobalt fluoride (CoF₂) nanoenzymes. This nanoadjuvant excelled in converting intratumoral H₂O₂ into reactive oxygen species (ROS), inducing cell pyroptosis. Its self-sustaining mechanism involved glucose depletion and continuous H₂O₂ generation, ensuring persistent catalytic activity. This metabolic manipulation and induction of oxidative stress significantly enhance pyroptosis in tumor cells. The released mtDNA subsequently activated the cGAS-STING pathway, with Co²⁺ further amplifying this effect. Notably, glucose-dependent TREX2 inhibition intensified cGAS-STING activation through metabolic regulation, leading to a strong immune response and tumor growth suppression. When combined with immune checkpoint blockade therapy, GOCoF₂ significantly inhibited primary and distant tumor progression via systemic immune activation. Additionally, we formulated GOCoF₂-lipiodol for transarterial embolization, which demonstrated superior efficacy in a rat model of orthotopic hepatocellular carcinoma. This study not only sheds light on the intricate relationship between tumor metabolism and immune regulation but also introduces a novel therapeutic approach for hepatocellular carcinoma.