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.
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