FLASH radiotherapy as an emerging paradigm in radioimmunotherapy: biological rationale, preclinical evidence, and translational roadmap.

Ultra-high dose rate radiotherapy (FLASH-RT) has emerged as a promising technology in recent years. Unlike conventional radiotherapy (CONV-RT), FLASH-RT delivers radiation at an ultra-high dose rate over a very short duration. This approach not only greatly shortens the treatment time, but also exhibits the "FLASH effect", which significantly spares healthy tissues while maintaining antitumor efficacy comparable to that of CONV-RT. Radiotherapy ignites immunity, fueling the radioimmunotherapy boom. However, even the most advanced radiotherapy techniques inevitably expose healthy tissue, immune organs, vasculature, and circulating or infiltrated lymphocytes to radiation-induced toxicity, limiting the synergistic effect of radioimmunotherapy. Notably, FLASH-RT offers a considerable alternative by protecting the immune system, converting the immunosuppressive tumor microenvironment (TME) into a moderately immune-infiltrated TME, and reducing immunosuppressive responses, thereby enhancing antitumor immunity. A growing number of studies have demonstrated that this combination shows synergistic antitumor effects even in drug-resistant tumor models. Despite these encouraging findings, the combination of FLASH-RT with immunotherapy remains in its early stages and has yet to reach clinical implementation. In this review, we present the current status, underlying mechanisms, and future prospects of FLASH-RT, with a particular focus on its immunomodulatory abilities and potential as a future platform for cancer radioimmunotherapy.