Targeting pyroptosis reverses KIAA1199-mediated immunotherapy resistance in colorectal cancer

作者：Lisha Li, Lei Zhao, Diwei Zhou, Yuanhang Yu, Peiyi Zhang, Jie Zheng, Zhenyu Lin, Dandan Yu, Jinghua Ren, Jing Zhang, Pengfei Zhou, Dejun Zhang, Tao� Zhang · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2025 · DOI：10.1136/jitc-2024-010000 · 被引用次数：10 · 研究领域：Inflammasome and immune disorders、Ferroptosis and cancer prognosis、Inflammatory Biomarkers in Disease Prognosis

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 + T cell infiltration....