Radiation dose-dependent skin toxicity and therapeutic advantage of FLASH radiotherapy via immune modulation.

BACKGROUND: FLASH radiotherapy shows promise in reducing normal tissue toxicity compared to conventional radiotherapy. Although several studies report skin-sparing effects of FLASH, few have quantitatively assessed this effect or explored underlying immunological mechanisms. METHODS: We quantified the skin-sparing effect of FLASH following single and fractionated hemithorax irradiation in mice. Multiplex gene expression analysis and immune profiling were performed to assess the immune status of irradiated skin. We also investigated the impact of CD8+ T-cell depletion for the different irradiation conditions. RESULTS: FLASH irradiation significantly delayed the onset and reduced the severity of skin toxicity compared to conventional irradiation for both single and fractionated irradiation (p<0.001), with a dose-modifying factor (DMF) of ≈1.5 following single dose irradiation and a similar level of DMF (∼1.5) for fractionated irradiation. FLASH irradiated mice showed dampened immune activation and greater preservation of immune cell populations. CD8+ T-cell depletion exacerbated skin toxicity and inflammatory response following conventional but not FLASH irradiation. CONCLUSION: Conventional radiation-induced skin toxicity is dose dependent and strongly linked to subsequent immune dysfunction, with stronger toxicity under immunocompromised conditions. FLASH irradiation provides significant reduction in skin toxicity, an effect maintained with hypofractionated regimens and in immunocompromised conditions. These findings underscore the clinical potential of FLASH radiotherapy, where normal tissue toxicity limits treatment and reveal an immune-mediated contribution to its protective effect.