Bacteroides fragilis toxin in colorectal tumors activates STAT3 and drives microsatellite instability

Colorectal cancer (CRC) remains a global malignancy with over 1.9 million new cases annually. Emerging evidence implicates enterotoxigenic <i>Bacteroides fragilis</i> (ETBF) and its toxin (BFT) in activating STAT3 and promoting microsatellite instability (MSI), a novel microbial oncogenic axis. In analyses of more than 1200 CRC tumors, <i>B. fragilis</i> abundance correlated with a 2.14-fold higher MSI-high frequency and increased CpG island methylator phenotype. Mechanistically, BFT triggers E-cadherin cleavage, β-catenin activation, and IL-6/IL-17 up-regulation, fostering inflammation, oxidative stress, and mismatch-repair suppression. Animal models demonstrate a more than 60% rise in tumor burden following ETBF colonization, while human studies show <i>B. fragilis</i> present in about 80% of CRC tissues versus 50% of controls. These findings establish BFT-induced STAT3 signaling as a driver of genomic instability and tumor evolution. Targeting this pathway offers new prospects for biomarker development and precision therapy in colorectal cancer.