Abstract

Pyroptosis holds great promise for evoking robust anti‐tumor immunity, but many pyroptosis induction strategies rely on caspase‐3 (Casp‐3) activation and face challenges of the immunosuppressive nature of apoptosis and the frequent silencing of gasdermin E (GSDME), a substrate of Casp‐3, in tumors. Here, we report a strategy to rewire the pyroptotic pathway by bypassing Casp‐3 to directly activate gasdermin D (GSDMD). We identify a small‐molecule agonist, (E)‐2,3‐diiodobut‐2‐ene‐1,4‐diol (DIBDO), which undergoes deiodination to release iodide ions upon activation by the tumor‐abundant nucleophile glutathione, thereby catalytically generating singlet oxygen and molecular iodine. This cascade induces oxidative damage that downregulates key mediators of caspase‐9 and caspase‐8 pathways, thereby down‐regulating Casp‐3 activation. This mechanism selectively triggers GSDMD‐mediated pyroptosis, provoking robust immunogenic cell death and inflammatory cytokine release to reconfigure the tumor immune microenvironment. In murine tumor models, DIBDO enhances tumor infiltration of cytotoxic T cells and synergizes with checkpoint blockade therapy to suppress both primary and distal tumors. It can also serve as an in situ or exogenous vaccine to elicit potent and durable antitumor immunity. This work presents a paradigm‐shifting approach to cancer immunotherapy by decoupling pyroptosis from Casp‐3 dependence, offering a promising avenue to expand the scope of immunogenic cell death‐based treatments. This work introduces a small‐molecule agonist, DIBDO, that bypasses Casp‐3 to directly trigger GSDMD‐mediated pyroptosis in tumors. Activated by glutathione, DIBDO generates singlet oxygen and molecular iodine, blocking Casp‐3 pathways and inducing immunogenic cell death. This reconfigures the tumor microenvironment, transforms the tumor cells into in situ or exogenous vaccine, offering a novel paradigm for cancer immunotherapy.