Human Organoids in Radiation Research: Modeling Tissue Injury, Regeneration and Therapeutic Response

Radiation therapy is a cornerstone in the treatment of abdominal, pelvic, thoracic, head and neck and central nervous system malignancies. However, irradiation inevitably damages adjacent normal tissues, leading to radiation-induced enteritis, lung injury, cardiac injury, salivary gland dysfunction and brain injury, which compromise both quality of life and treatment outcomes. Traditional two-dimensional cell cultures and animal models have significant limitations in mimicking human tissue radiation responses: the former lacks three-dimensional architecture and cell–cell interactions, while the latter exhibits species-specific differences. In recent years, three-dimensional organoid technology has rapidly emerged as a powerful platform in radiation biology and radiation oncology. In particular, organoids derived from patient tissues or induced pluripotent stem cells (hiPSCs) offer key advantages, including self-organization capacity and near-physiological tissue structure and function, which have greatly advanced in-depth research in the radiation field. This review comprehensively summarizes applications of human organoids in radiation injury and regeneration research across the brain, heart, lung, esophagus, salivary gland, intestine, muscle, thyroid, hematopoietic system, and tumors. Animal-derived and organotypic models are included only as comparative or supporting mechanistic evidence and are explicitly identified as such. We focus on advances in modeling radiation injury, elucidating regenerative mechanisms, screening radioprotective and radiosensitizing agents and predicting patient responses to chemoradiation. Current limitations and future directions are discussed collectively at the end.