IFN-I signaling enhances salivary gland stem and progenitor cell activity after irradiation

The goal of radiotherapy in cancer treatment is to maximize DNA damage in tumors while minimizing harm to surrounding healthy tissues, especially to stem and progenitor cells essential for tissue regeneration and organ function. Here, we investigated the molecular responses to photon and proton irradiation, two key modalities in head and neck cancer treatment. Multiomics and in vitro analyses revealed that both photon and proton irradiation of mouse salivary gland organoids induced similar early responses, including DNA damage, micronuclei formation, increased amounts of the cytosolic DNA sensor cGAS, and type I interferon (IFN-I) signaling. In addition, both types of radiation induced comparable increases in the release of mitochondrial DNA (mtDNA) into the cytoplasm and stimulated the production of ZBP1, a cytosolic nucleic acid sensor involved in mtDNA recognition. However, proton irradiation resulted in a more pronounced loss of heterochromatin regulators and derepression of transposable elements at later times after irradiation, which was accompanied by increased accumulation of intracellular double-stranded RNA (dsRNA) and an enhanced RIG-I-mediated IFN-I response. Genetic and pharmacological modulation demonstrated its critical role for IFN-I signaling in enhancing salivary gland stem and progenitor cell activity after irradiation in vitro and in vivo. Our findings reveal more pronounced molecular changes after proton irradiation as compared with photon irradiation and uncover a proregenerative role of IFN-I signaling in the salivary gland, suggesting this pathway as a promising therapeutic target to mitigate radiation-induced side effects.