Spatiotemporal Charging Single‐Atom Nanozymes Activated Pyroptosis for Antitumor Immunotherapy via Bioorthogonal Disruption of Succination and Reinvigorating T Lymphocytes

Abstract Pyroptosis can trigger strong immunogenic cell death (ICD) of tumor cells for antitumor immunotherapy. However, metabolic disorders of fumarate in the tumor microenvironment (TME) can significantly reduce the pyroptosis rate and render T lymphocytes dysfunctional. Here, the ultrasound (US)‐driven piezoelectric charges assisted Fe‐based SAzyme (BFTM) with co‐loaded triphenylphosphonium (TPP) and methyl (Z)‐4‐(chloro(2‐phenylhydrazono)methyl)benzoate (MMB, a bioorthogonal reagent of fumarate) for activating pyroptosis and regulating fumarate metabolism is developed. Positive and negative charges generated by barium titanate (BTO) regulate the electron cloud density of single‐Fe atom, endowing the BFTM with efficient reactive oxygen species (ROS) production ability for triggering caspase‐1 related gasdermin D (GSDMD) mediated pyroptosis. Meanwhile, the consumption of intracellular fumarate through bioorthogonal reaction not only prevented the succinate of cysteines in GSDMD, causing it to be activated and oligomerized by caspase‐1 to enhance pyroptosis but also restored the phosphorylation of ZAP70 to normalize the T cell receptor (TCR) signaling pathways for reinvigorating CD8 + T cells. In short, US‐driven BFTM as a pyroptosis initiator and metabolism immune activator significantly enhances antitumor immunotherapy effects via ROS storms, fumarate depletion, triggering pyroptosis, and reinvigorating T lymphocytes.