Induction of cytoplasmic dsDNA and cGAS-STING immune signaling after exposure of breast cancer cells to X-rays or high energetic carbon ions

Radiotherapy can trigger activation of the cGAS-STING axis via cytoplasmic dsDNA fragment induction. The activation of cGAS–STING initiates innate immune signaling mediated by interferon type-I that can contribute to eradicate the malignancy. The effect was shown to depend on the fractionation scheme employed. We hypothesized that the innate immune response can also depend on radiation quality because densely ionizing radiation, such as carbon ions, have different effects on DNA lesion quality. We show here that carbon ions induced a significantly higher yield of cytosolic dsDNA fragments per unit dose as compared to photons in an in vitro 4T1 breast cancer model. The higher efficiency also translated in expression and release of interferon-β by the tumor cells. Cytoplasmic dsDNA fragments as well as interferon-β release increased with doses up to 24 Gy and no differences for a fractionation scheme (3x8 Gy) were found as compared to the single high doses of photons. In conclusion, we found that the release of interferon-β after radiation is increasing with the radiation dose up to 20 Gy and that carbon ions have the potential to elicit a strong innate immune signaling.