Year: 2026
Type: preprint
Abstract: Ultrahigh dose-rate FLASH radiotherapy spares normal tissue while preserving antitumor activity, positioning it as a promising technology in radiation oncology, but its immunomodulatory mechanisms remain elusive. Here, using a bilateral subcutaneous tumor model in mice, we show that 8-Gy FLASH X-rays, versus an equal dose of conventional dose-rate (CONV) X-rays, elicit a robust abscopal antitumor effect with anti-PD-1 therapy. Single-cell transcriptome and T cell receptor (TCR) profiling reveal that FLASH X-rays plus anti-PD-1 enhance antitumor immune infiltration and TCR clonal expansion in both irradiated and abscopal tumor lesions. Mechanistically, the ultrashort temporal continuity of FLASH dose delivery conserves chromatin compaction in neutrophils during exposure and inhibits neutrophil extracellular trap (NET) formation, thereby dismantling NET-mediated CD8 + T-cell exclusion within primary tumors. Conversely, CONV or split-dose FLASH X-rays induce marked chromatin modifications prior to dose completion, leading to chromatin hyper-relaxation which promotes NETosis and consequently abrogates systemic antitumor immunity. Notably, this detrimental effect can be reversed by pharmacologically suppressing PARylation-mediated chromatin modification and decondensation in neutrophils. These findings identify radiation-induced aberrant chromatin relaxation in neutrophils as a critical determinant of radioimmunotherapy outcomes, providing a rationale for redefining the FLASH effect and advancing its clinical translation.
Authors: Xiaolin Shi, Si Qiu, Yiwei Yang, Yongchao Jiang, Jianxin Wang, Xiaofeng Ding, Yufan He, Meiqi Lv, Hongyan Li, Qing Li, Baosheng Li, Zheng Zhou, Kui Zhou, Dexin Xiao, Peng Li, Chuanyu Cao, Lijun Shan, Yu Liu, Tingting Wang, Feng Gao, Caiyong Ye, Congchong Yan, Ji Huang, Yuan Wang, Guangsheng Shi, Fengjuan Jiang, Yuqi Xiao, Hongdao Qu, Xun Jin, Jianghong Zhang, Yan Pan, Yang Bai, Feng Xi, Liang Wu, Xiaobo Du, Jianheng Zhao, Jian Wang, Min Xie, Dai Wu, Chunlin Shao, Haowen Zhang
Institutions: Shanghai Medical College of Fudan University, Fudan University, Soochow University, State Key Laboratory of Radiation Medicine and Protection, BGI Research, Chongqing Medical University, China Academy of Engineering Physics, BGI Group (China), University of Electronic Science and Technology of China, Mianyang Central Hospital, National Institute of Metrology, Huashan Hospital, Fudan University Shanghai Cancer Center
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Cyrus Tang Foundation, National Natural Science Foundation of China, Chinese Academy of Sciences, China Academy of Engineering Physics, Soochow University, Shanghai University of Traditional Chinese Medicine, Priority Academic Program Development of Jiangsu Higher Education Institutions, State Key Laboratory of Radiation Medicine and Protection
OpenAlex ID: W7221589176