Harnessing Hyperthermia: Molecular, Cellular, and Immunological Insights for Enhanced Anticancer Therapies

Abstract

Hyperthermia, the raising of tumor temperature (≥39°C), holds great promise as an adjuvant treatment for cancer therapy. This review focuses on 2 key aspects of hyperthermia: its molecular and cellular effects and its impact on the immune system. Hyperthermia has profound effects on critical biological processes. Increased temperatures inhibit DNA repair enzymes, making cancer cells more sensitive to chemotherapy and radiation. Elevated temperatures also induce cell cycle arrest and trigger apoptotic pathways. Furthermore, hyperthermia modifies the expression of heat shock proteins, which play vital roles in cancer therapy, including enhancing immune responses. Hyperthermic treatments also have a significant impact on the body's immune response against tumors, potentially improving the efficacy of immune checkpoint inhibitors. Mild systemic hyperthermia (39°C-41°C) mimics fever, activating immune cells and raising metabolic rates. Intense heat above 50°C can release tumor antigens, enhancing immune reactions. Using photothermal nanoparticles for targeted heating and drug delivery can also modulate the immune response. Hyperthermia emerges as a cost-effective and well-tolerated adjuvant therapy when integrated with immunotherapy. This comprehensive review serves as a valuable resource for the selection of patient-specific treatments and the guidance of future experimental studies.

Keywords: DNA repair; apoptosis; fever; heat shock protein; immune system; nanoparticle; thermal ablation.

Figure 1.

Physiological and molecular effects of hyperthermia. Mild hyperthermic therapy elevates blood flow, tumor perfusion, and oxygenation, thereby amplifying the effectiveness of chemotherapy drug delivery, radiotherapy, and the antitumor immune response. Elevated temperatures due to heat shock impede DNA repair mechanisms, resulting in an increased occurrence of replication errors, cell cycle arrest, and apoptosis. Conversely, the increased expression of heat shock proteins (HSPs) in response to protein damage and aggregation can induce thermotolerance, potentially counteracting the beneficial effects of hyperthermia. Thermal ablation initiates necrotic cell death, leading to the release of tumor antigens. This process facilitates antigen presentation and activates immune cells. Mild hyperthermia and heat shock also lead to immune response but in a non-necrotic way.

Figure 2.

The immunomodulatory effect of hyperthermia. Therapy-resistant tumors often employ strategies to evade the antitumor immune response, resulting in the creation of an immunosuppressive microenvironment. This environment is characterized by the prevalence of tolerogenic dendritic cells (DC), M2 macrophages, and regulatory T cells (Treg). However, mild hyperthermia can counteract these immune-suppressing mechanisms by enhancing the infiltration and activation of immune cells. Mild hyperthermia also promotes neutrophil degranulation, phagocytosis, and antigen presentation in M1 macrophages and dendritic cells. Following the uptake of antigens, dendritic cells migrate to lymph nodes, where they present tumor antigens to T cells. This process leads to the clonal expansion of cytotoxic T cells (Tc), which subsequently infiltrate tumors. Alongside natural killer cells (NK), these cytotoxic T cells work to eliminate cancer cells by releasing cytotoxic granules and activating the Fas-FasL pathway.