Gemella morbillorum promotes colorectal tumorigenesis through barrier disruption and invasion-dependent DNA damage.

Bacteria are increasingly recognized as contributors to cancer, yet the underlying mechanisms remain unclear for most species. Here, we find that Gemella morbillorum (Gm) is enriched in feces and tumor tissues from patients with colorectal cancer (CRC) and reveal a multi-step host-pathogen mechanism that promotes colorectal tumorigenesis. In mouse models of CRC, Gm suppresses IL-22 production by type 3 innate lymphoid cells (ILC3s), impairing intestinal barrier function and facilitating bacterial translocation to early neoplastic lesions. At the tumor site, Gm utilizes an ANXA2-dependent, clathrin-mediated pathway to invade CRC cells. Gm induces profound lipid remodeling, characterized by the accumulation of oxidation-prone fatty acids and enhanced lipid peroxidation, which contributes to invasion-dependent DNA damage. Inhibition of lipid peroxidation attenuates Gm-induced DNA damage, functionally linking lipid oxidative stress to genotoxicity. Together, these findings identify Gm as a candidate onco-pathogen in CRC that uses multiple mechanisms to disarm the intestinal barrier and trigger genotoxicity.