Current Views on Mechanisms of the FLASH Effect in Cancer Radiotherapy

FLASH radiotherapy (FLASH-RT) is a new modality of radiotherapy by delivering doses with ultra-high dose rates. FLASH-RT has the ability to suppress tumor growth while sparing normal tissues, known as the FLASH effect. Although FLASH effect has proved valid in various models by different ionizing radiations, the exact underlying mechanism is still unclear. This article summarizes mainstream hypotheses of FLASH effect at physicochemical and biological levels, including oxygen depletion and free radical reactions, nuclear and mitochondria damage, as well as immune response. These hypotheses contribute reasonable explanations to the FLASH effect, and are interconnected according to the chronological order of the organism's response to ionizing radiation. By collating the existing consensus, evidence, and hypotheses, this article provides a comprehensive overview of potential mechanisms of FLASH effect and practical guidance for future investigation in the field of FLASH-RT.