Thermal radiosensitization beyond misrepair: a mechanistic model of temperature-enhanced DNA vulnerability

<i>Objective.</i>Hyperthermia treatment (HT), characterized by elevated tissue temperatures above physiological levels, is a well-established radiosensitizer. When combined with radiotherapy (RT), forming thermoradiotherapy (TRT), a synergistic effect is observed across<i>in vitro</i>,<i>in vivo</i>, and clinical studies. The greatest radiosensitization occurs when HT and RT are applied simultaneously. This work aims to explore physical mechanisms-beyond DNA repair inhibition-that contribute to this synergy.<i>Approach.</i>We developed a biophysical model for the thermal enhancement ratio (TER), incorporating temperature-dependent variations in the number of vulnerable DNA sites, the DNA-ion/particle interaction cross-section, and other physicochemical parameters. These include ion production rate, diffusion processes, and medium density. The model includes misrepair effects phenomenologically, that make it consistent with other studies.<i>Main results.</i>The model reproduces TER values observed under simultaneous HT and RT in isolated plasmids with variable temperature. Our results indicate that, in addition to misrepair, other physical factors contribute to radiosensitization under concurrent treatment. Among these, the temperature-dependent amplification of DNA-ion/particle interaction cross-section-driven by enhanced DNA thermal fluctuations structure-emerges as the second most influential factor.<i>Significance.</i>These findings suggest that thermal radiosensitization arises not only from impaired repair, but also from increased physical vulnerability of the DNA. The model provides mechanistic insight for optimizing TRT parameters.