FLASH X-rays preserve neutrophil chromatin to boost antitumor immunity
- 1State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University
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.
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BibTeX
@misc{shi2026flash,
title = {{FLASH X-rays preserve neutrophil chromatin to boost antitumor immunity}},
author = {X. Shi and S. Qiu and Y. Yang and Y. Jiang and J. Wang and X. Ding and Y. He and M. Lv and H. Li and Q. Li and B. Li and Z. Zhou and K. Zhou and D. Xiao and P. Li and C. Cao and L. Shan and Y. Liu and T. Wang and F. Gao and C. Ye and C. Yan and J. Huang and Y. Wang and G. Shi and F. Jiang and Y. Xiao and H. Qu and X. Jin and J. Zhang and Y. Pan and Y. Bai and F. Xi and L. Wu and X. Du and J. Zhao and J. Wang and M. Xie and D. Wu and C. Shao and H. Zhang},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.11.758276},
url = {https://www.biorxiv.org/content/10.64898/2026.10.11.758276v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - FLASH X-rays preserve neutrophil chromatin to boost antitumor immunity
AU - X. Shi
AU - S. Qiu
AU - Y. Yang
AU - Y. Jiang
AU - J. Wang
AU - X. Ding
AU - Y. He
AU - M. Lv
AU - H. Li
AU - Q. Li
AU - B. Li
AU - Z. Zhou
AU - K. Zhou
AU - D. Xiao
AU - P. Li
AU - C. Cao
AU - L. Shan
AU - Y. Liu
AU - T. Wang
AU - F. Gao
AU - C. Ye
AU - C. Yan
AU - J. Huang
AU - Y. Wang
AU - G. Shi
AU - F. Jiang
AU - Y. Xiao
AU - H. Qu
AU - X. Jin
AU - J. Zhang
AU - Y. Pan
AU - Y. Bai
AU - F. Xi
AU - L. Wu
AU - X. Du
AU - J. Zhao
AU - J. Wang
AU - M. Xie
AU - D. Wu
AU - C. Shao
AU - H. Zhang
PY - 2026
DA - 2026/10/11
PB - bioRxiv
DO - 10.64898/2026.10.11.758276
UR - https://www.biorxiv.org/content/10.64898/2026.10.11.758276v1
AB - 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.
ER -