Self-Cascaded Pyroptosis-STING Initiators for Catalytic Metalloimmunotherapy

作者：Qiao Yu, Shumin Sun, Nailin Yang, Zifan Pei, Youdong Chen, Jihu Nie, Huali Lei, Li Wang, Fei Gong, Liang Cheng · 发表于：Journal of the American Chemical Society · 年份：2025 · DOI：10.1021/jacs.4c12552 · 被引用次数：111 · 研究领域：interferon and immune responses、Nanoplatforms for cancer theranostics、Toxoplasma gondii Research Studies

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 (CoF 2 ) nanocatalysts for catalytic metalloimmunotherapy. CoF 2 nanocatalysts with a semiconductor structure and enzyme-like activity generated a substantial amount of reactive oxygen species (ROS) under stimulation by endogenous H 2 O 2 and exogenous ultrasound. Importantly, we discovered that Co-based nanomaterials themselves induce pyroptosis in cancer cells. Therefore, CoF 2 nanocatalysts initially acted as pyroptosis inducers, triggering caspase-1/GSDMD-dependent pyroptosis in cancer cells via Co 2+ and ROS, leading to mtDNA release. Subsequently, CoF 2 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 impede...