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.