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As a major gastrointestinal malignancy, colon cancer (CC) demands more effective therapies. Gene therapy is an emerging promising strategy, and pyroptosis, a novel lytic cell death form, serves as a vital antitumor target, with Gasdermin D (GSDMD)-a key pore-forming protein in pyroptosis-showing anti-CC potential. We constructed an engineered attenuated Salmonella strain to deliver a GSDMD-expressing plasmid, and verified its therapeutic efficacy via in vitro and in vivo studies. In CC cell lines, the Salmonella vector upregulated GSDMD and cleaved caspase-1 (its upstream activator), inhibiting cell proliferation and inducing pyroptosis. In CC-bearing mice, the strain significantly suppressed tumor progression, reduced Ki67 expression, elevated intratumoral GSDMD and cleaved caspase-1 levels, and enhanced CD4⁺ and CD8⁺ T cell infiltration to boost antitumor immunity. This study suggests that attenuated Salmonella-mediated GSDMD delivery combats CC by triggering pyroptosis and stimulating antitumor immunity, laying a foundation for GSDMD-targeted gene therapeutics.