BACKGROUND AND AIMS: Chronic inflammation in inflammatory bowel disease (IBD) patients represents a risk factor for developing colitis-associated cancer (CAC). We previously linked the endoplasmic reticulum unfolded protein response (UPRER) signal transducer activating transcription factor 6 (ATF6) with spontaneous microbiota-dependent colonic adenoma development in mice expressing epithelial-specific activated ATF6 (nATF6IEC). METHODS: To investigate IBD-related risk factors in ATF6-mediated tumorigenesis, we crossed tumor-free monoallelic (tg/wt) nATF6IEC mice with interleukin-10 deficient mice (Il10-/-). We characterized our newly generated murine model under germ-free (GF) and specific pathogen-free (SPF) conditions, including tumor phenotype and immune cell characterizations, as well as complex human stool and minimal consortium colonizations. RESULTS: IL-10 deficiency initiated tumor susceptibility, with 77% of 12-week tg/wt;Il10-/- mice developing colonic adenomas and invasive carcinomas in this novel CAC mouse model. Tumor formation correlated with mucosal immune cell infiltration, characterized by CD11b+ granulocytes and monocytes, and mucosa-associated dysbiosis. Colonization of germ-free nATF6IEC;Il10-/- mice with minimal biosynthetic consortia and IBD stool re-established CAC, confirming microbiota-dependent ATF6-driven tumorigenesis. Increased ATF6 expression in IBD patients during active disease highlights human relevance. CONCLUSION: Our findings show that IBD susceptibility heightens the risk for ATF6-driven tumorigenesis.