Temperature-Dependent Effects of Induced Hyperthermia, Including Whole-Body Hyperthermia, on the Hallmarks of Cancer:...

Background/Objectives: Cancer's complexity can be rationalized through the "hallmarks of cancer," which define the key biological capabilities driving malignancy. Induced hyperthermia-an adjunctive therapy that elevates body temperature above the normal setpoint for a defined period-has been explored for its modulatory effects on these hallmarks. This systematic review aims to evaluate the effects and mechanisms of induced hyperthermia on tumor cells through the established hallmarks of cancer framework. Methods: A systematic search following the Cochrane guidelines and PRISMA assessment tool was conducted in PubMed and Cochrane Library (2000-2025) to identify reviews on the effects of induced hyperthermia on cancer hallmarks. Studies' predefined inclusion criteria were independently evaluated by two external teams and graded using PRISMA standards. Results: From the 2015 records screened, 103 studies met the inclusion criteria. Evidence indicates that induced hyperthermia modulates seven of the ten cancer hallmarks. The most well-supported mechanisms of action include (1) the immune system activation (39-41 °C)-enhancing antigen presentation, activating innate/adaptive immune cells, promoting tumor infiltration-and (2) genome instability and mutation (41 °C)-impairing DNA repair pathways and increasing tumor vulnerability. Both hallmarks provide evidence clarifying the mechanistic pathways through which induced hyperthermia exerts its effects. Conclusions: Induced hyperthermia exerts multifaceted, temperature-dependent effects on cancer biology, predominantly through immune activation and genomic destabilization. While it enhances the therapeutic sensitivity of other treatment modalities (e.g., chemotherapy, radiotherapy) and antitumor responses, excessive heating may induce immune suppression and thermotolerance. Optimizing temperature parameters and identifying biomarkers are essential for integrating hyperthermia into targeted and multimodal cancer therapies.