A tumor-resident Staphylococcus epidermidis strain exhibits genomic and metabolic traits driving hepatocellular carcinoma progression

<h2>Summary</h2> Although bacteria have been detected in hepatocellular carcinoma (HCC), the low microbial biomass has hindered isolation of viable intratumoral strains and evaluation of their functional relevance. Intratumoral microbiota profiling by 5R 16S rRNA sequencing, together with a stringent contamination-controlled workflow, identified enrichment of <i>Staphylococcus</i> in advanced-stage (Barcelona Clinic Liver Cancer [BCLC] C) HCC and enabled isolation of a viable <i>S. epidermidis</i> strain, GX3-2, from HCC tissue. GX3-2 promoted HCC cell proliferation and migration <i>in vitro</i> and was associated with accelerated xenograft growth in a pilot intratumoral inoculation model. Multi-omics analyses linked GX3-2 to distinct metabolic features, including adenosine and 2-phenylethylamine (2-PEA), together with host transcriptional programs related to cell cycle and epithelial-mesenchymal transition. These findings provide proof-of-concept evidence that a tumor-derived <i>S. epidermidis</i> isolate may modulate malignant phenotypes in HCC.