URI-driven DNA damage triggers DNA-sensing signaling in colorectal cancer

Colorectal cancer (CRC) is a highly prevalent malignancy and a major cause of cancer-related mortality. Most CRC subtypes, particularly those driven by chromosomal instability, respond poorly to immunotherapy, which highlights the need for new therapeutic targets capable of improving antitumor immune responses. The unconventional RPB5 interactor (URI) is an oncogene overexpressed in CRC and has been linked to DNA repair, genomic stability, and tumor development, suggesting that it may influence both tumor progression and tumor-associated immune signaling. In this study, we investigated the role of URI in colorectal tumorigenesis and in DNA damage-associated innate immune activation using genetically engineered mouse models and human CRC cell lines. We observed that heterozygous loss of URI significantly reduced tumor burden in both Lgr5-CreERT2 and Villin-CreERT2 APC deletion models, indicating that URI is critical for the maintenance of colorectal tumorigenesis. Tumors from URI-deficient mice showed higher levels of γ-H2AX, reflecting an increased DNA double-strand break. This genomic damage was accompanied by a consistent increase in type I interferons and some specific interferon-stimulated genes, suggesting activation of cGAS–STING signaling in vivo. In human colorectal cancer cell lines, URI siRNA-mediated depletion failed to trigger cGAS–STING pathway under basal conditions. Although irradiation substantially increased DNA damage, especially in URI-depleted HT-29 cells, it did not elicit a robust interferon response, indicating that full activation of this pathway requires a supportive tumor microenvironment and appropriate temporal kinetics for signaling accumulation. Together, these findings identify URI as an important regulator of genomic stability and colorectal tumor development. By linking URI loss to DNA damage accumulation and subsequently cGAS–STING activation in vivo, this work suggests that URI influences the balance between genomic instability and innate immune responsiveness in CRC, highlighting its role in shaping how tumors engage with DNA-sensing pathways.