<jats:title>Abstract</jats:title> <jats:p>Stimulator of IFN genes (STING) is an innate immune sensor for cytosolic cyclic dinucleotides and also serves as an adaptor molecule for a number of intracellular DNA sensors. While STING has been shown to be critically involved in modulating immune responses during infections and autoimmune diseases, its physiological role in cancer remains largely unknown. In this study, we demonstrated that STING-deficient mice are highly susceptible to colitis-associated colorectal cancer with overt intestinal proliferation during early stages of tumorigenesis. Hyperactive NF-kB and STAT3 signaling was responsible for increased levels of proinflammatory cytokines observed in STING-deficient mice. Furthermore, intestinal tissues deficient in STING exhibited elevated level of DNA damage maker, γH2AX and a defect in caspase-1-mediated colonic IL-18 release, highlighting its fundamental functions in maintaining genomic integrity and activating inflammasome. Therefore, our results identify an unexpected and important role for STING in mediating protection against colorectal tumorigenesis.</jats:p>