Transposable Element Derepression-mediated IFN-I Signaling Enhances Stem/Progenitor Cell Activity After Irradiation

Radiotherapy is a mainstay in cancer treatment, aiming to maximize DNA damage in tumors while minimizing harm to surrounding healthy tissues. However, the collateral damage to normal tissues, especially stem/progenitor cells essential for tissue regeneration and organ function, remains a significant challenge. Here, we investigate the molecular responses to photon and proton irradiation, two key modalities in head and neck cancer treatment, using organoids. Multiomics analysis reveals a stronger double-stranded RNA (dsRNA)-induced type I interferon (IFN-I) response following proton irradiation, driven by loss of heterochromatin regulators and derepression of transposable elements (TEs). This response, mediated by the cytoplasmic sensor RIG-I, enhances the inflammatory signaling initiated by the canonical dsDNA sensors cGAS and ZBP1. Genetic and pharmacological modulation of IFN-I signaling in vitro and in vivo demonstrates its critical role in enhancing stem/progenitor cell activity post-irradiation. Our findings reveal a pro-regenerative role of TE derepression-mediated IFN-I response suggesting this pathway as a promising therapeutic target to mitigate radiation-induced side effects. Teaser Transposable element-mediated type I interferon signaling enhances stem/progenitor cell activity after irradiation.