Mechanisms underlying FLASH radiotherapy, a novel way to enlarge the differential responses to ionizing radiation between normal and tumor tissues

Different from conventional radiotherapy (CONV-RT), FLASH radiotherapy (FLASH-RT) delivers a single high dose at a mean dose rate ≥40 ​Gy/s in milliseconds to achieve similar tumor control to CONV-RT while sparing normal tissues from detrimental injury. It provides an intriguing perspective in improving clinical outcomes for tumor patients as well as a novel way to enhance the differential responses between normal and tumor tissues. However, its mechanisms remain largely unclear. In this paper, we review the currently available publications on FLASH-RT and parse the probable mechanisms of three major aspects including the production of reactive oxygen species, DNA damage response, and immunoreaction. Experiments specifically designed to disclose the intrinsic difference between normal and malignant cells in response to FLASH-RT and CONV-RT are necessary to prove these hypotheses.