Intratumoral bacterium Enterocloster bolteae promotes hepatocellular carcinoma progression by directly binding tumor cells.

The gut microbiota regulates systemic metabolism, inflammation, and immunity, with evidence linking microbiota translocation through the gut-liver axis to hepatocellular carcinoma (HCC) progression. However, the specific bacteria and underlying mechanisms driving tumor progression remain unexplored. We identify that E. bolteae is enriched in the feces of HCC patients and is associated with poor prognosis. E. bolteae disrupts intestinal barrier integrity, translocates to the liver, and promotes tumor proliferation. Mechanistically, we show that E. bolteae's surface protein, penicillin-binding transpeptidase domain-containing protein (PbpT), directly interacts with the tumor cell receptor desmoglein 1 (DSG1), facilitating bacterial adhesion and attenuating DSG1's tumor-suppressive function. Additionally, this interaction activates the mitogen-activated protein kinase (MAPK) signaling pathway to accelerate HCC progression. Blockade of PbpT abrogates E. bolteae attachment and its role in promoting HCC progression. These findings identify the PbpT-DSG1-MAPK axis as a critical driver of HCC progression. Targeting PbpT may be a promising therapeutic strategy for HCC.