Integrative Multiomics and Single‐Cell Analyses Identify FKBP10 as a Predictor of Radiotherapy Outcome in Colorectal Cancer

Background Radiotherapy resistance limits colorectal cancer (CRC) treatment efficacy, with only 15%–20% of patients achieving a complete response. Validated biomarkers predicting treatment response and serving as therapeutic targets are critically needed. Methods We performed integrative multiomics analysis of 200 CRC patients (GSE87211) with independent validation in 58 patients (GSE46862). Single‐cell RNA sequencing of 63,689 cells (GSE132465) determined cell‐type‐specific expression. Functional validation was conducted in radiotherapy‐resistant CRC cell lines through loss‐of‐function experiments including proliferation, migration/invasion, and radiosensitivity assays. Results FKBP10 emerged as the only gene achieving statistical significance in both discovery (log2FC = 0.74, p = 0.0007) and validation (log2FC = 0.52, p = 0.032) cohorts among 48 radioresistance‐associated genes. Single‐cell profiling revealed that FKBP10 was predominantly expressed in cancer‐associated fibroblasts (CAFs, 51.5% of stromal cells), implicating CAF‐mediated stromal remodeling in resistance. FKBP10 knockdown significantly inhibited proliferation, colony formation (35%–40% reduction), migration (30%), and invasion (50%), while markedly enhancing radiosensitivity through increased DNA damage ( γ H2AX foci increased twofold, p < 0.01) and strand breaks (comet tail DNA: 22% → 43%, p < 0.01). Conclusions This multiomics study establishes FKBP10 as a robust CAF‐derived biomarker and functional therapeutic target for radiotherapy resistance in CRC, providing a foundation for developing FKBP10‐targeted combination strategies for precision cancer treatment.