Hyperthermia (HT) combined with irradiation is a well-known concept to improve the curative potential of radiotherapy. Technological progress has opened new avenues for thermoradiotherapy, even for recurrent head and neck squamous cell carcinomas (HNSCC). Preclinical evaluation of the curative radiosensitizing potential of various HT regimens remains ethically, economically, and technically challenging. One key objective of our study was to refine an advanced 3-D assay setup for HT + RT research and treatment testing. For the first time, HT-induced radiosensitization was systematically examined in two differently radioresponsive HNSCC spheroid models using the unique in vitro “curative” analytical endpoint of spheroid control probability. We further investigated the cellular stress response mechanisms underlying the HT-related radiosensitization process with the aim to unravel the impact of HT-induced proteotoxic stress on the overall radioresponse. HT disrupted the proteome’s thermal stability, causing severe proteotoxic stress. It strongly enhanced radiation efficacy and affected paramount survival and stress response signaling networks. Transcriptomics, q-PCR, and western blotting data revealed that HT + RT co-treatment critically triggers the heat shock response (HSR). Pre-treatment with chemical chaperones intensified the radiosensitizing effect, thereby suppressing HT-induced Hsp27 expression. Our data suggest that HT-induced radiosensitization is adversely affected by the proteotoxic stress response. Hence, we propose the inhibition of particular heat shock proteins as a targeting strategy to improve the outcome of combinatorial HT + RT.

The immune system plays a vital role in cancer control, yet its efficacy is often compromised by tumor-induced immunosuppression. Moderate hyperthermia (\(39-42^{\circ }\)C) can enhance immune responses and improve therapeutic outcomes. This work investigates how mild hyperthermia modulates tumor-immune dynamics through a mathematical modeling approach. Specifically, we analyze how heat-induced reduction in tumor proliferation and enhancement of immune recruitment affect tumor control outcomes. We extend the Kuznetsov model of tumor-immune interactions by incorporating thermal effects on two key parameters: tumor growth rate and immune cell recruitment rate. A bifurcation analysis is performed to characterize how the system’s equilibrium structure changes as these parameters vary. Our analysis shows that the tumor–immune system has critical points where small changes in tumor growth or immune response can dramatically alter outcomes. Moderate hyperthermia can shift these tipping points in favor of the immune system, making it more likely that the tumor is controlled rather than escapes immune surveillance. In practical terms, hyperthermia expands the conditions under which immune-mediated tumor suppression is successful and reduces the scenarios that would lead to tumor progression, effectively improving the chances of therapeutic control. These results provide quantitative insight into how transient hyperthermia can reshape tumor-immune dynamics, increasing the likelihood of immune-mediated tumor suppression. The model suggests that moderate hyperthermia, by simultaneously reducing tumor proliferation and enhancing immune recruitment, can shift tumor-immune interactions toward control in a subset of initial conditions. Thus, it offers a theoretical framework supporting the use of hyperthermia as an immunomodulatory adjuvant in cancer therapy, particularly in combination with immunotherapeutic strategies.

Objective. Mathematical modeling can offer valuable insights into the behavior of biological systems upon treatment. Different mathematical models (empirical, semi-empirical, and mechanistic) have been designed to predict the efficacy of either hyperthermia (HT), radiotherapy (RT), or their combination. However, mathematical approaches capable of modeling cell survival from shared general principles for both mono-treatments alone and their co-application are rare. Moreover, some cell cultures show dose-dependent saturation in response to HT or RT, manifesting in survival curve flattenings. An advanced survival model must, therefore, appropriately reflect such behavior. Approach. We propose a mathematical approach to model the effect of both treatments based on the general principle of sublethal damage (SLD) accumulation for the induction of cell death and irreversible proliferation arrest. Our approach extends Jung’s model on heat-induced cellular inactivation by incorporating dose-dependent recovery rates that delineate changes in SLD restoration. Main results. The resulting unified model (Umodel) accurately describes HT and RT survival outcomes, applies to simultaneous thermoradiotherapy modeling, and is particularly suited to reproduce survival curve flattening phenomena. We demonstrate the Umodel’s robust performance (R2 0.95) based on numerous clonogenic cell survival data sets from the literature and our experimental studies. Significance. The proposed Umodel allows using a single unified mathematical function based on generalized principles of accumulation of SLD with implemented radiosensitization, regardless of the type of energy deposited and the mechanism of action. It can reproduce various patterns of clonogenic survival curves, including any flattening, thus encompassing the variability of cell reactions to therapy, thereby potentially better reflecting overall tumor responses. Our approach opens a range of options for further model developments and strategic therapy outcome predictions of sequential treatments applied in different orders and varying recovery intervals between them.

Photosynthesis converts sunlight into chemical energy through networks of pigment–protein complexes that operate reliably under warm, noisy, and highly variable environmental conditions. Over the past decades, advances in spectroscopy and physically grounded modeling have shown that excitation energy transfer in these systems is governed by quantum-mechanical interactions shaped by environmental fluctuations. However, understanding photosynthetic function requires placing these microscopic processes within the broader context of natural illumination, where incoherent sunlight and multiple interacting timescales drive photosynthetic systems toward dynamically stabilized operating regimes. Under these conditions, ultrafast excitonic and vibronic dynamics remain relevant at short spatial and temporal scales, while overall photosynthetic behavior emerges from the interplay between energy transfer, dissipation, photoprotection, and adaptation under fluctuating environmental conditions. Building on this physical picture, this Perspective discusses photosynthetic function as a robust energy-management process shaped by evolutionary adaptation to natural illumination. Across bacteria, cyanobacteria, algae, and plants, photosynthetic systems operate under common physical constraints, including the stochastic nature of sunlight, finite excitation-transfer and charge-separation rates, thermal fluctuations, and the need to avoid photodamage under variable irradiance. These constraints influence the temporal organization of excitation transport, dissipation, and photoprotective responses. In this view, photosynthetic function depends not only on efficient excitation transfer, but also on maintaining stable and adaptable energy flow across changing environmental conditions. By integrating quantum physics, biological regulation, and ecological variability, this interdisciplinary perspective highlights how physical constraints shape robust photosynthetic function under realistic environmental conditions.

Objective: Hyperthermia (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 in vitro, in vivo, 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. Approach: 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, which make it consistent with other studies. Main results: 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. Significance: 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.

Objective. 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 in vitro , in vivo , 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. Approach. 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. Main results. 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. Significance. 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.