Influence of LET on Low-dose Radiation Responses: Signatures of Hyper-radiosensitivity after High-LET Irradiation.

Hyper-radiosensitivity refers to increased cellular sensitivity at low doses of ionizing radiation and is not accurately captured by classical radiobiological models. Although predominantly studied in the context of low-LET radiation, such as photons, its behavior under high-LET conditions remains less well characterized. In this work, we introduce an analytical formulation of the minimum mutation load (MML) model. This model explains hyper-radiosensitivity and induced radioresistance as a self-protective tissue strategy that minimizes long-term mutational burden by selectively eliminating heavily damaged cells. Overall cell survival can then be modeled as the product of two independent mechanisms: conventional radiation-induced cell killing, described by the linear-quadratic (LQ) model, and programmed cell death, governed by mutation load minimization, as captured by the MML framework. To extend the model to high-LET radiation, we integrate the local effect model (LEM), which predicts the LET dependence of both cell survival and mutation induction. This combined approach is applied to a curated dataset of 93 experimental survival curves and validated against ion irradiation data for helium and carbon ions. A key result is the progressive compression of hyper-radiosensitivity and induced radioresistance with increasing LET, where the characteristic transition from increased to decreased cell survival at low doses shifts to an initial steeper decline in survival without recovery. Because low-dose ion irradiation data remain scarce, we discuss the model assumptions considering corresponding biological evidence.