Recapitulating the tumour microenvironment: advancing personalised radiation therapy through organoid technology

The efficacy and resistance of tumor radiotherapy are profoundly influenced by the complex tumor microenvironment (TME). However, traditional preclinical models have limitations in accurately simulating the heterogeneity and dynamic interactions of the human TME, hindering the development of TME-targeted radiosensitization strategies. Organoid technology, as a revolutionary three-dimensional in vitro model, faithfully recapitulates the histological architecture, cellular diversity, and genetic characteristics of primary tumors. This provides a powerful platform for investigating the impact of the TME on radiotherapy response within a system that highly mimics physiological/pathological conditions. This review systematically elaborates on how organoid technology guides tumor radiotherapy by modeling key components of the TME. We begin by outlining the features of organoid technology and its advantages in recapitulating TME heterogeneity. Subsequently, we delve into the latest applications of organoid models in deciphering how key factors within the TME—such as cell-cell interactions, immune cell functions, stromal components, and hypoxic conditions—influence radiotherapy response. Furthermore, this article summarizes the progress in using organoid technology to study radiosensitivity across different tumor types and highlights its great potential, particularly when integrated with multi-omics technologies, for uncovering mechanisms of radiotherapy resistance. Based on this research, we emphasize the clinical translation prospects of organoid technology as a functional platform for guiding personalized radiotherapy strategies, including dose screening and combination therapy. Finally, we objectively discuss the current technical challenges faced by these models, including standardization, vascularization, immunocompetence, and clinical integration, and offer perspectives on future optimization directions and their broad clinical application potential. In conclusion, organoid technology holds promise for reshaping the research paradigm of tumor radiotherapy and advancing the era of individualized precision radiotherapy.