Ultra-high dose rate and high-LET effects on DNA damage distribution in 3D genome: a predictive mechanistic model for cell survival in FLASH irradiation

High-LET beams such as helium and carbon ions have been investigated in FLASH radiotherapy, introducing LET as an essential variable for mechanistic exploration. Nevertheless, most existing FLASH mechanistic models are limited to low-LET irradiation, while current high-LET models rely on empirical oxygen enhancement ratio formulations and lack mechanistic interpretability. To disentangle unresolved FLASH mechanisms from high-LET effects, a decoupled framework is presented to predict cell survival during high-LET FLASH irradiation. This framework decouples two key components: dose-rate-independent cellular responses, which are modeled by 3D genome-based DNA damage distribution; and dose-rate-dependent changes in DNA damage, which are quantified using the proposed Probability Modifying Factor (PMF). PMF values are derived from oxygen depletion and radical recombination hypotheses, with experimentally measured LET-dependent radical yields. Dose modification factor (DMF)-LET curves were calculated for protons, helium, carbon, and neon ions under FLASH irradiation. Due to the scarcity of direct high-LET FLASH experimental data, multi-perspective validations were performed against plasmid DNA, cancer cells, and OER-LET measurements, verifying the model’s capability to describe radical recombination, oxygen depletion, and high-LET cellular responses. DMF remains appreciable across the intermediate LET range, suggesting that a pronounced FLASH effect is also predicted in the spread-out Bragg peak (excluding the distal end). The model’s predictions align with experiments. This prediction is consistent with the experimental observation of FLASH effects in the SOBP region of ion beams. The proposed decoupled framework enables mechanistic extension and quantitative prediction of the FLASH effect for ion beams, advancing fundamental understanding and supporting future translational applications of high-LET FLASH radiotherapy.