What is it about?

Tumor immunotherapy synergized with radiotherapy (RT) becomes promising for eradicating multiple advanced tumors. However, accompanying treatment-related detrimental events in normal tissues have been the dark side of the combination regimen. In the present study, the pioneering application of ultra-high dose rate FLASH irradiation in radioimmunotherapy was made to counteract the intestinal toxicity induced by conventional dose rate (CONV) irradiation in the context of programmed cell death ligand-1 (PD-L1) blockade.

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Why is it important?

Based on our study, the split-new ‘DNA integrity’ hypothesis was proposed to elucidate the mechanism of the FLASH sparing effect, indicating the coming of a new era of FLASH irradiation. The hypothesis indicated that the “relatively intact DNA integrity” within intestinal cells during the “instantaneous” IR exposure was critical for FLASH X-ray in sparing PD-L1–deficient mice from detrimental enteritis. Unlike the classic "Oxygen depletion" hypothesis, our theory could elaborate the FLASH effect of tumor cells since numerous DNA fragments were provoked and released into the cytoplasm of tumor cells even during FLASH radiation due to the intrinsic genome instability, which subsequently activated the cGAS-STING system and initiated systemic antitumor responses as CONV RT did.


Based on our theory, the mean dose rate might somewhat be more pivotal than the currently recognized instantaneous dose rate in eliciting the “FLASH effect”, which might be crucial for optimizing of clinical applications and developing suitable accelerators.

Haowen Zhang
Soochow University

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This page is a summary of: FLASH X-ray spares intestinal crypts from pyroptosis initiated by cGAS-STING activation upon radioimmunotherapy, Proceedings of the National Academy of Sciences, October 2022, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.2208506119.
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