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

(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 O2 diffusivities, acidosis- and heat-related enhanced O2 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 O2 tensions in tumors.