BACKGROUND: Despite advancements in treatment modalities, several patients with colorectal cancer (CRC) remain unresponsive to immune checkpoint inhibitor therapy. Pyroptosis, an inflammatory programmed cell death process, holds substantial promise for tumor immunotherapy. In this study, we explored the use of pyroptosis to overcome immunotherapy resistance in CRC. METHODS: We used a pyroptosis-related gene panel to construct an immunotherapy efficacy evaluation model and validated its performance by immunohistochemical staining of CRC patient samples. Pyroptosis and its underlying mechanisms were examined both in vitro and in vivo using PCR, western blotting, lactate dehydrogenase release assay, ELISA, co-immunoprecipitation, immunohistochemistry, fluorescence cell assays, microscopic imaging, flow cytometry analysis and bioinformatics approaches. RESULTS: We established a model to define high or low levels of pyroptosis in CRC, revealed that low pyroptosis led to immunotherapy resistance, and identified KIAA1199 as a characteristic protein of low pyroptosis CRC. We further demonstrated that KIAA1199 contributes to low pyroptosis, resulting in resistance to immunotherapy. Mechanistically, KIAA1199 bound to and stabilized DNA methyltransferase-1 (DNMT1), thereby inhibiting GSDME-mediated pyroptosis. Importantly, our study highlighted that decitabine reversed KIAA1199-mediated immunotherapy resistance by enhancing pyroptosis to restore IL-1B release and CD8 CONCLUSIONS: We found a critical role of KIAA1199 in promoting immunotherapy resistance by suppressing pyroptosis via the DNMT1/GSDME pathway in CRC. Decitabine has emerged as a promising therapeutic agent for reversing KIAA1199-mediated immunotherapy resistance by enhancing pyroptosis. Our findings provide valuable insights for enhancing the efficacy of immunotherapy in patients with CRC who exhibit resistance to conventional immunotherapy approaches.