Novel FGFR Inhibitor Combined with Radiotherapy Induces GSDME-Dependent Pyroptosis to Amplify Immunogenic Cell Death Improving Anti-Tumor Activity.

Multiple preclinical and clinical studies have shown that combining fibroblast growth factor receptor (FGFR) inhibitors with radiotherapy enhances antitumor efficacy. However, progress in this combination strategy remains constrained by persistent acquired resistance due to the hypoxia-induced immunosuppressive tumor microenvironment (TME). Herein, we designed and synthesized a series of dual-functional compounds by conjugating the oxygen-mimicking moiety 2-methyl-5-nitroimidazole with the FGFR inhibitor Erdafitinib. Among these derivatives, compound 19e exhibited potent antitumor activity and radiosensitization in HCT116 and SNU-16 xenograft models. Mechanistic studies demonstrated that 19e, when combined with radiotherapy, synergistically activated the ROS-Caspase-3-GSDME axis, downregulated PD-L1 expression, and induced immunogenic cell death (ICD). These combined effects thereby enhanced tumor sensitivity to radiotherapy. Collectively, the findings support 19e as a potential therapeutic agent for the treatment of malignant tumors.