Self-Cascaded Pyroptosis-STING Initiators for Catalytic Metalloimmunotherapy

Abstract

Gasdermin (GSDM)-mediated pyroptosis involves the induction of mitochondrial damage and the subsequent release of mitochondrial DNA (mtDNA), which is anticipated to activate the cGAS-STING pathway, thereby augmenting the antitumor immune response. However, challenges lie in effectively triggering pyroptosis in cancer cells and subsequently enhancing the cGAS-STING activation with specificity. Herein, we developed intelligent self-cascaded pyroptosis-STING initiators of cobalt fluoride (CoF₂) nanocatalysts for catalytic metalloimmunotherapy. CoF₂ nanocatalysts with a semiconductor structure and enzyme-like activity generated a substantial amount of reactive oxygen species (ROS) under stimulation by endogenous H₂O₂ and exogenous ultrasound. Importantly, we discovered that Co-based nanomaterials themselves induce pyroptosis in cancer cells. Therefore, CoF₂ nanocatalysts initially acted as pyroptosis inducers, triggering caspase-1/GSDMD-dependent pyroptosis in cancer cells via Co²⁺ and ROS, leading to mtDNA release. Subsequently, CoF₂ nanocatalysts were further utilized as intelligent STING agonists that were specifically capable of detecting mtDNA and augmenting the activation of the cGAS-STING pathway. These cascade events triggered a robust immune response, effectively modulating the immunosuppressive tumor microenvironment into an immune-supportive state, thereby providing favorable support for antitumor therapy. This innovative strategy not only significantly impeded the growth of the primary tumor but also elicited an immune response to further augment the efficacy of immune checkpoint inhibitors in preventing distant tumor progression. Overall, this study proposed a self-cascade strategy for activating and amplifying the cGAS-STING pathway with specificity mediated by pyroptosis, representing a valuable avenue for future cancer catalytic metalloimmunotherapy.