Modulating the Heat Stress Response to Improve Hyperthermia-Based Anticancer Treatments

SIMPLE SUMMARY: Hyperthermia is a method to expose a tumor to elevated temperatures. Heating of the tumor promotes the effects of various treatment regimens that are based on chemo and radiotherapy. Several aspects, however, limit the efficacy of hyperthermia-based treatments. This review provides an overview of the effects and limitations of hyperthermia and discusses how current drawbacks of the therapy can potentially be counteracted by inhibiting the heat stress response—a mechanism that cells activate to defend themselves against hyperthermia. ABSTRACT: Cancer treatments based on mild hyperthermia (39–43 °C, HT) are applied to a widening range of cancer types, but several factors limit their efficacy and slow down more widespread adoption. These factors include difficulties in adequate heat delivery, a short therapeutic window and the acquisition of thermotolerance by cancer cells. Here, we explore the biological effects of HT, the cellular responses to these effects and their clinically-relevant consequences. We then identify the heat stress response—the cellular defense mechanism that detects and counteracts the effects of heat—as one of the major forces limiting the efficacy of HT-based therapies and propose targeting this mechanism as a potentially universal strategy for improving their efficacy.