Abstract
FLASH radiotherapy (FLASH-RT), characterized by ultra-high dose rate irradiation (≥40 Gy/s), has generated substantial interest in radiation oncology due to its reported capacity to preserve normal tissues while maintaining tumor control-a phenomenon termed the "FLASH effect." This review synthesizes current advances in FLASH-RT, emphasizing its core biological mechanisms, including radiolytic oxygen depletion, free radical recombination, immune modulation, DNA integrity preservation, and vascular normalization. Furthermore, we explore the synergistic potential of FLASH-RT combined with immunotherapy strategies such as immune checkpoint inhibitors (ICIs), CAR-T cells, and cancer vaccines. Preclinical evidence indicates that FLASH-RT reduces lymphodepletion, enhances CD8(+) T cell infiltration, and downregulates immunosuppressive factors (e.g., TGF-β and PD-L1), thereby overcoming limitations of conventional radiotherapy (CONV-RT) and amplifying antitumor immunity. Early-phase clinical trials (e.g., FAST-01, IMPULSE) have demonstrated preliminary safety and efficacy, yet challenges remain in mechanistic elucidation, technological standardization, and regulatory approval. Current evidence is predominantly derived from preclinical models, and conflicting data exist regarding tissue-specific FLASH effects (e.g., protection absent in gonads). Moreover, the synergistic mechanisms with immunotherapy remain largely hypothetical, supported by limited in vivo studies. By addressing these barriers through interdisciplinary collaboration, FLASH-RT may eventually advance precision radio-immunotherapy, but substantial translational research is still required before it can supplant conventional paradigms.