From gut-liver axis hijacking to intratumoral microbiota establishment: mechanisms and therapeutic opportunities in hepatocellular carcinoma

Hepatocellular carcinoma (HCC), the predominant form of liver cancer, remains a leading cause of global cancer mortality. Recent evidence indicates that intratumoral bacteria reside within HCC tumors, largely originating from the gut. Disruption of the intestinal barrier, coupled with impaired hepatic immune clearance, enables gut-derived microbes to translocate to the liver via the portal vein. Within the tumor microenvironment, these bacteria remain metabolically active and interact directly with host cellular receptors, thereby activating oncogenic signaling cascades, modulating local immune responses, and inducing epigenetic alterations. Notably, distinct bacterial signatures correlate consistently with tumor stage, prognosis, and therapeutic response. This review aims to provide a comprehensive update on the role of intratumoral bacteria in HCC, elucidate their mechanistic involvement in tumor development, and explore the potential of microbiome-targeted strategies for advancing diagnostic and therapeutic modalities.