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Here, we report a strategy to rewire the pyroptotic pathway by bypassing Casp\u20103 to directly activate gasdermin D (GSDMD). We identify a small\u2010molecule agonist, (E)\u20102,3\u2010diiodobut\u20102\u2010ene\u20101,4\u2010diol (DIBDO), which undergoes deiodination to release iodide ions upon activation by the tumor\u2010abundant nucleophile glutathione, thereby catalytically generating singlet oxygen and molecular iodine. This cascade induces oxidative damage that downregulates key mediators of caspase\u20109 and caspase\u20108 pathways, thereby down\u2010regulating Casp\u20103 activation. This mechanism selectively triggers GSDMD\u2010mediated 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\u2010shifting approach to cancer immunotherapy by decoupling pyroptosis from Casp\u20103 dependence, offering a promising avenue to expand the scope of immunogenic cell death\u2010based treatments.<\/jats:p>","DOI":"10.1002\/advs.76655","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T11:42:15Z","timestamp":1784806935000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rewiring Pyroptosis to Potentiate Cancer Immunotherapy via a Gasdermin D Agonist Bypassing Caspase\u20103"],"prefix":"10.1002","volume":"13","author":[{"given":"Dan","family":"Zhao","sequence":"first","affiliation":[{"name":"National Engineering Research Center for Nanomedicine College of Life Science and Technology and Key Laboratory of Molecular Biophysics of the Ministry of Education Huazhong University of Science and Technology  Wuhan 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Science and Technology and Key Laboratory of Molecular Biophysics of the Ministry of Education Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9274-1866","authenticated-orcid":false,"given":"Liang","family":"Luo","sequence":"additional","affiliation":[{"name":"National Engineering Research Center for Nanomedicine College of Life Science and Technology and Key Laboratory of Molecular Biophysics of the Ministry of Education Huazhong University of Science and Technology  Wuhan China"},{"name":"Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica School of Chemistry and Chemical Engineering Huazhong University of Science and Technology  Wuhan China"},{"name":"Hubei Key Laboratory of Bioinformatics and Molecular Imaging College of Life Science and Technology and Key Laboratory of Molecular Biophysics of the Ministry of Education Huazhong University of Science and 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