Targeting pyroptosis reverses KIAA1199-mediated immunotherapy resistance in colorectal cancer

• DOI: 10.1136/jitc-2024-010000
• Publication Date: 2025-02-26T06:31:05Z
• Authors: Lisha Li; Lei Zhao; Diwei Zhou; Yuanhang Yu; Peiyi Zhang; Jinge Zheng; Zhenyu Lin; Dandan Yu; Jinghua Ren; Jing Zhang; Pengfei Zhou; Dejun Zhang; Tao Zhang
• Keywords: Pyroptosis; Cancer Immunotherapy

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 overcome immunotherapy resistance CRC. Methods We used a pyroptosis-related gene panel construct efficacy evaluation model and validated its performance by immunohistochemical staining CRC patient samples. Pyroptosis underlying mechanisms were examined both vitro vivo using PCR, western blotting, lactate dehydrogenase release assay, ELISA, co-immunoprecipitation, immunohistochemistry, fluorescence assays, microscopic imaging, flow cytometry analysis bioinformatics approaches. Results established define high or low levels CRC, revealed that led resistance, identified KIAA1199 as characteristic protein further demonstrated contributes pyroptosis, resulting Mechanistically, bound stabilized DNA methyltransferase-1 (DNMT1), thereby inhibiting GSDME-mediated pyroptosis. Importantly, our study highlighted decitabine reversed KIAA1199-mediated enhancing restore IL-1B CD8 + T infiltration. Conclusions found critical role promoting suppressing via DNMT1/GSDME pathway Decitabine has emerged promising therapeutic agent reversing Our findings provide valuable insights who exhibit conventional