Radiation-induced immune response in novel radiotherapy approaches FLASH and spatially fractionated radiotherapies

The last several years have revealed increasing evidence of the immunomodulatory role of radiation therapy. Radiotherapy reshapes the tumoral microenvironment can shift the balance toward a more immunostimulatory or immunosuppressive microenvironment. The immune response to radiation therapy appears to depend on the irradiation configuration (dose, particle, fractionation) and delivery modes (dose rate, spatial distributions). Although an optimal irradiation configuration (dose, temporal fractionation, spatial dose distribution, etc.) has not yet been determined, temporal schemes employing high doses per fraction appear to favor radiation-induced immune response through immunogenic cell death. Through the release of damage-associated molecular patterns and the sensing of double-stranded DNA and RNA breaks, immunogenic cell death activates the innate and adaptive immune response, leading to tumor infiltration by effector T cells and the abscopal effect. Novel radiotherapy approaches such as FLASH and spatially fractionated radiotherapies (SFRT) strongly modulate the dose delivery method. FLASH-RT and SFRT have the potential to trigger the immune system effectively while preserving healthy surrounding tissues. This manuscript reviews the current state of knowledge on the immunomodulation effects of these two new radiotherapy techniques in the tumor, healthy immune cells and non-targeted regions, as well as their therapeutic potential in combination with immunotherapy.