Organoids in Precision Radiotherapy: Methodological Foundations, Tumor-Specific Evidence, and Translational Roadmaps.

BACKGROUND: Radiotherapy remains a cornerstone of cancer treatment, while its efficacy is often limited by tumor radioresistance and the risk of normal tissue toxicity. Conventional preclinical models, including two-dimensional (2D) cell cultures and murine xenografts, exhibit significant limitations in recapitulating human tumor pathophysiology, thereby impeding the clinical translation of novel radiotherapeutic strategies. Patient-derived organoids (PDOs) have emerged as transformative three-dimensional (3D) ex vivo models that recapitulate key aspects of original tumor heterogeneity and are increasingly applied in oncology research. METHODS: This article provides a comprehensive review of the literature on the application of PDOs in radiation oncology, with a focused analysis of their pathway toward clinical translation. RESULTS: PDOs demonstrate significant utility in predicting radiosensitivity, elucidating radioresistance mechanisms, optimizing combination therapies, modeling radiation injury, and screening targeted drugs. The integration of organoid technology with microfluidic organ-on-a-chip (OoC) platforms also offers unprecedented capability to dynamically simulate the tumor microenvironment and conduct high-throughput dose-response studies. A translational roadmap is presented for leveraging these biomimetic systems to advance personalized radiotherapy, ultimately aiming to accelerate the clinical translational application of organoids. CONCLUSIONS: Despite challenges in standardization and immune component recapitulation, PDOs represent a powerful platform for advancing personalized radiotherapy.