Combined Radiotherapy and Hyperthermia: A Systematic Review of Immunological Synergies for Amplifying Radiation-Induced Abscopal Effects

Abstract

Introduction: The abscopal effect is a systemic immune response characterized by metastases regression at sites distant from the irradiated lesion. This systematic review aims to explore the immunological mechanisms of action underlying the abscopal effect and to investigate how hyperthermia (HT) can increase the chances of radiotherapy (RT) triggering systemic anti-tumor immune responses.

Methods: This review is created in accordance with the PRISMA guidelines.

Results and conclusion: HT and RT have both complementary and synergistic immunological effects. Both methods trigger danger signal release, promoting cytokine and chemokine secretion, which increases T-cell infiltration and facilitates cell death. Both treatments upregulate extracellular tumor HSP70, which could amplify DAMP recognition by macrophages and DCs, leading to stronger tumor antigen presentation and CTL-mediated immune responses. Additionally, the combined increase in cell adhesion molecules (VCAM-1, ICAM-1, E-selectin, L-selectin) could enhance leukocyte adhesion to tumors, improving lymphocyte trafficking and boosting systemic anti-tumor effects. Lastly, HT causes vasodilation and improves blood flow, which might exacerbate those distant effects. We suggest the combination of local radiotherapy with fever-range whole-body hyperthermia to optimally enhance the chances of triggering the abscopal effect mediated by the immune system.

Keywords: cancer; hyperthermia; immune system; metastasis; radiotherapy.

Figure 1

Prisma flowchart of the included studies.

Figure 2

DAMP release induced by RT and its subsequent recognition by an immune cell. RT (indicated by the lightning bolt) triggers the presentation of ATP, calreticulin (CRT) and high-mobility group box 1 (HMG1) from the tumor cell. The released DAMPs bind to purinergic receptors on the surface of the immune cell, initiating a signaling cascade that enhances the immune cell’s ability to recognize and respond to the tumor cell. This interaction is crucial for the activation and recruitment of immune cells to the tumor microenvironment, thereby boosting the anti-tumor immune response.

Figure 3

Activation of the cGAS-STING pathway by radiation therapy. Radiation therapy (indicated by the lightning bolt) causes the release of cytosolic DNA within the cell. This DNA is detected by the cyclic GMP-AMP synthase (cGAS), which then produces cyclic GMP-AMP (cGAMP). cGAMP binds to the stimulator of interferon genes (STING) on the endoplasmic reticulum, leading to its activation. Activated STING recruits and activates TANK-binding kinase 1 (TBK1), which in turn phosphorylates interferon regulatory factor 3 (IRF-3). Phosphorylated IRF-3 translocates to the nucleus, where it promotes the production of type I interferons (IFNs). These interferons are then secreted from the cell, enhancing the immune response by promoting the recruitment and activation of immune cells. Additionally, TREX1, a DNA exonuclease that degrades cytosolic DNA regulates this pathway.

Figure 4

Schematic representation of the immune response induced by radiation and hyperthermia therapy. This figure illustrates the synergistic effects of hyperthermia (indicated by the little flames) and radiation therapy (indicated by the black and yellow circles) in enhancing the immune response within the tumor microenvironment and beyond. Radiation therapy activates the cGAS/STING pathway, enhancing immune recognition, T-cell trafficking, T-cell recruitment, and chemokine secretion. Radiation also normalizes blood vasculature, induces the expression of pro-inflammatory cytokines, stimulates antigen presentation, and increases the sensitivity of tumor cells to immune responses. Hyperthermia further amplifies these effects by increasing immune recognition and T-cell trafficking, as well as promoting the secretion of chemokines. The combination of hyperthermia and radiation therapy leads to an enhanced presentation of tumor antigens, which activates natural killer (NK) cells, T-cells, and helper T-cells (Th-cells). This combined approach effectively strengthens the anti-tumor immune response, providing a more robust attack on the tumor cells.