Unraveling the dual nature of FLASH radiotherapy: From normal tissue sparing to tumor control

Abstract

FLASH radiotherapy (FLASH-RT), characterized by the delivery of ultra-high dose rate irradiation within microseconds to milliseconds, has rapidly emerged as a paradigm-shifting approach in radiation oncology. Preclinical studies have consistently demonstrated its remarkable ability to spare normal tissues while maintaining effective tumor control, challenging long-standing paradigms of radiobiology. This review comprehensively synthesizes current experimental findings from diverse in vitro and in vivo models, including zebrafish embryos, mice, Drosophila melanogaster, and Caenorhabditis elegans, emphasizing the distinct protective effects of FLASH-RT across various tissue types. Potential mechanistic hypotheses—such as radiolytic oxygen depletion, radical recombination, immune modulation, mitochondrial dynamics, and preservation of DNA integrity—are critically evaluated to illuminate the biological foundations of the FLASH effect. Furthermore, the influence of key technical parameters, including radiation modality, total dose, dose rate, and fractionation schemes, alongside biological determinants such as tissue radiosensitivity and tumor heterogeneity, is systematically analyzed. Despite the promising preclinical evidence, major challenges persist in optimizing radiation delivery protocols, unraveling the precise biological mechanisms, and translating these findings into clinical practice. As a highly anticipated and transformative therapeutic innovation, FLASH-RT holds tremendous potential to redefine the future of cancer treatment; however, its underlying mechanisms remain elusive and continue to be a focal point of intensive multidisciplinary research.