From Localized Mild Hyperthermia to Improved Tumor Oxygenation: Physiological Mechanisms Critically Involved in Oncologic Thermo-Radio-Immunotherapy

SIMPLE SUMMARY: Mild hyperthermia (mHT, 39–42 °C) is a potent modality when combined with existing radio-, chemo-, or immunotherapy, leading to enhanced microcirculatory blood flow and improved tumor oxygenation. Currently, the mechanisms responsible for these mHT-related effects are not fully understood, and the extent and kinetics of therapy-promoting changes are not yet completely clarified. Herein, we review and discuss mHT-induced biological mechanisms that are relevant to radio-oncology and immunotherapy. The short-term increase in tumor perfusion induced by mHT may be caused by vasodilation of co-opted vessels and upstream normal tissue vasculature, as well as decreases in viscous resistance to flow. More sustained effects seem to result from a reduction in interstitial fluid pressure and VEGF-triggered angiogenesis. Increased microcirculatory tumor blood flow after mHT seems to be the prime driver for the enhanced tumor oxygenation, and this is supported by increasing O(2) diffusivities and O(2) extraction and facilitated O(2) unloading from oxyhemoglobin due to right-shifts of the HbO(2)-dissociation curve by hyperthermia per se and intensified tumor acidosis. ABSTRACT: (1) Background: Mild hyperthermia (mHT, 39–42 °C) is a potent cancer treatment modality when delivered in conjunction with radiotherapy. mHT triggers a series of therapeutically relevant biological mechanisms, e.g., it can act as a radiosensitizer by improving tumor oxygenation, the latter generally believed to be the commensurate result of increased blood flow, and it can positively modulate protective anticancer immune responses. However, the extent and kinetics of tumor blood flow (TBF) changes and tumor oxygenation are variable during and after the application of mHT. The interpretation of these spatiotemporal heterogeneities is currently not yet fully clarified. (2) Aim and methods: We have undertaken a systematic literature review and herein provide a comprehensive insight into the potential impact of mHT on the clinical benefits of therapeutic modalities such as radio- and immuno-therapy. (3) Results: mHT-induced increases in TBF are multifactorial and differ both spatially and with time. In the short term, changes are preferentially caused by vasodilation of co-opted vessels and of upstream normal tissue vessels as well as by improved hemorheology. Sustained TBF increases are thought to result from a drastic reduction of interstitial pressure, thus restoring adequate perfusion pressures and/or HIF-1α- and VEGF-mediated activation of angiogenesis. The enhanced oxygenation is not only the result of mHT-increased TBF and, thus, oxygen availability but also of heat-induced higher O(2) diffusivities, acidosis- and heat-related enhanced O(2) unloading from red blood cells. (4) Conclusions: Enhancement of tumor oxygenation achieved by mHT cannot be fully explained by TBF changes alone. Instead, a series of additional, complexly linked physiological mechanisms are crucial for enhancing tumor oxygenation, almost doubling the initial O(2) tensions in tumors.