Wang Yu, Qi Shu-Nan, Bi Nan, Li Ye-Xiong
Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China.
Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China.
Transl Oncol. 2025 Jan;51:102183. doi: 10.1016/j.tranon.2024.102183. Epub 2024 Nov 28.
FLASH ultra-high dose rate radiotherapy (RT) can effectively exert the protective effect on normal tissue and reduce the risk of treatment-related toxicity, without compromising the killing effect on tumor tissue, resulting in a significant differential biological effect between tumor control and normal tissue damage, namely the FLASH effect. To date, the precise biological details of the FLASH effect remain uncertain. The currently mainstream mechanisms proposed by the academic community include the transient oxygen depletion hypothesis, free radical hypothesis, immune protection hypothesis, and DNA integrity hypothesis, which have attracted increasing attention in recent years. Based on these theoretical principles and numerous investigations on the FLASH effect in vivo and in vitro, the combined application of FLASH and immune checkpoint inhibitors (ICIs) has been considered synergistic and potentially practical. The primary underlying basis is that FLASH might actively preserve the number and function of circulating immune cells, thereby enhancing the efficacy of immune cell-mediated immunotherapy. Meanwhile, FLASH RT could activate the tumor immune microenvironment and transform "cold'' tumors into ''hot'' ones, consequently boosting local and systemic anti-tumor immunity and expanding the therapeutic benefits of ICIs. Moreover, FLASH might attenuate immunoinflammatory responses and minimize the incidence of radiation-related adverse events, allowing for the potentially safer and promising clinical application of combing FLASH RT with ICI therapy. Nevertheless, data on this treatment modality is currently lacking, and several barriers remain to be addressed, including the logistical bottlenecks, technical hurdles, limited availability, and unclear biological mechanisms. Further research is warranted in the future.
FLASH超高剂量率放疗（RT）可有效对正常组织发挥保护作用，降低治疗相关毒性风险，同时不影响对肿瘤组织的杀伤效果，从而在肿瘤控制与正常组织损伤之间产生显著的生物学效应差异，即FLASH效应。迄今为止，FLASH效应的确切生物学细节仍不明确。学术界目前提出的主流机制包括瞬时氧耗竭假说、自由基假说、免疫保护假说和DNA完整性假说，近年来这些假说受到了越来越多的关注。基于这些理论原则以及对FLASH效应的大量体内和体外研究，FLASH与免疫检查点抑制剂（ICI）的联合应用被认为具有协同作用且具有潜在的实用性。其主要潜在依据是，FLASH可能积极维持循环免疫细胞的数量和功能，从而增强免疫细胞介导的免疫治疗效果。同时，FLASH放疗可激活肿瘤免疫微环境，将“冷”肿瘤转变为“热”肿瘤，进而增强局部和全身抗肿瘤免疫力，扩大ICI的治疗益处。此外，FLASH可能减轻免疫炎症反应，降低辐射相关不良事件的发生率，使得FLASH放疗与ICI治疗联合应用在临床上具有潜在的安全性和前景。然而，目前关于这种治疗方式的数据尚缺乏，仍有几个障碍有待解决，包括后勤瓶颈、技术障碍、可用性有限以及生物学机制不明确等。未来有必要进行进一步的研究。
