Patient-Derived Organoids as a Platform to Decipher and Overcome Radioresistance: From the Tumor Microenvironment to Radiosensitizer Discovery

Patient-derived organoids (PDOs) preserve patient genotypes and 3D architecture, offering a useful platform to investigate mechanisms of radioresistance and test radiosensitizers. We outline an end-to-end workflow—model establishment, multi-omics profiling, pharmacologic screening, and in vivo confirmation—and spotlight immune-competent, vascularized, and organ-on-chip formats. PDOs reveal actionable mechanisms across DNA damage response, hypoxia–metabolic and immune remodeling, and radiation-induced senescence, enabling rational radiosensitizer selection. Paired tumor–normal organoids concurrently gauge efficacy and normal tissue toxicity, refining the therapeutic index. Remaining gaps (incomplete microenvironment, fractionation modeling, and standardization) are being addressed via reporting standards and co-clinical studies, positioning PDOs to support precision radiotherapy.