The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer

Abstract

Radiotherapy is a major modality used to combat a wide range of cancers. Classical radiobiology principles categorize ionizing radiation (IR) as a direct cytocidal therapeutic agent against cancer; however, there is an emerging appreciation for additional antitumor immune responses generated by this modality. A more nuanced understanding of the immunological pathways induced by radiation could inform optimal therapeutic combinations to harness radiation-induced antitumor immunity and improve treatment outcomes of cancers refractory to current radiotherapy regimens. Here, we summarize how radiation-induced DNA damage leads to the activation of a cytosolic DNA sensing pathway mediated by cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING). The activation of cGAS–STING initiates innate immune signaling that facilitates adaptive immune responses to destroy cancer. In this way, cGAS–STING signaling bridges the DNA damaging capacity of IR with the activation of CD8+ cytotoxic T cell-mediated destruction of cancer—highlighting a molecular pathway radiotherapy can exploit to induce antitumor immune responses. In the context of radiotherapy, we further report on factors that enhance or inhibit cGAS–STING signaling, deleterious effects associated with cGAS–STING activation, and promising therapeutic candidates being investigated in combination with IR to bolster immune activation through engaging STING-signaling. A clearer understanding of how IR activates cGAS–STING signaling will inform immune-based treatment strategies to maximize the antitumor efficacy of radiotherapy, improving therapeutic outcomes.

Combination of Immune Checkpoint Inhibitors and Radiotherapy for Advanced Non-Small-Cell Lung Cancer and Prostate Cancer: A Meta-Analysis

“…Radiation induces antitumor T cells, complementing the activity of ICI [ 38 , 39 ]. Radiation may also activate the antitumor immune response by triggering the stimulation of the interferon gene (STING)-mediated DNA sensing pathway [ 40 , 41 ]. Hou et al demonstrated that the deficiency of noncanonical NF- κ B promotes radiation-induced antitumor immunity by regulating the STING-mediated type I IFN expression [ 42 ].…”

Exploring the optimal dose of low ionizing radiation to enhance immune function: a rabbit model

“…Their functions are phagocytosis, sterilization, secretion of inflammatory factors, and tumor suppression, which are important roles in the immune response. 21 Macrophages play an important role in non-specific immunity, and participate in in vivo anti-infection, anti-tumor, and immune regulation processes. The strength of the phagocytosis can affect immune function.…”

Role of Mitochondria in Radiation Responses: Epigenetic, Metabolic, and Signaling Impacts

“…As also stated in the excellent recent review by Storozynsky and Hitt [ 465 ], IR-induced DNA damage plays a very important role in IR-induced cGAS-STING-mediated immune responses to cancer. In fact, cytosolic mtDNA and also nDNA are recognized by cytosolic proteins, i.e., so-called inflammasomes belonging to the innate immune system [ 59 ].…”