Therapeutic Response-Driven Discrepancies in Intratumoral Microbiome Composition of Hepatocellular Carcinoma Following Conversion Therapy

Hepatocellular carcinoma, frequently detected late, constrains therapeutic interventions; contemporary conversion therapies enhance surgical eligibility and survival. While intratumoral microbiota is known to influence the tumor microenvironment, its alterations following therapeutic interventions remain underexplored. This study (NCT06365034) included patients with initially unresectable HCC using conversion therapy with two or three modalities: immune checkpoint inhibitors (ICIs), tyrosine kinase inhibitors (TKIs), and locoregional therapies such as transarterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC). Effectiveness indicators included conversion rate (38.1%), objective response rate (44.4%), disease control rate (90.1%), and radical (R0) resection rate (100%) and safety. Microbial profiling of hepatocellular carcinoma tissues stratified by pathological response to conversion therapy (major [pMajR] vs minor [pMinR] responders) revealed distinct ecological patterns. pMinR specimens exhibited higher α-diversity (Wilcoxon, p < 0.05) and β-diversity divergence (PCoA), with enrichment of Acidobacteriota/Chloroflexi phyla and Halomonas/Arthrobacter genera. pMajR tumors demonstrated dominance of Proteobacteria/Bacteroidetes phyla and elevated abundance of Escherichia-Shigella/Limosilactobacillus genera. Linear discriminant analysis Effect Size (LEfSe) analysis confirmed differential taxa (LDA > 3.0), while functional prediction based on PICRUSt2 indicated significant enrichments of methane metabolism/cofactor biosynthesis in pMinR and fatty acid synthesis pathways in pMajR. These findings suggest that the effectiveness of conversion therapy may be influenced by differences in microbiota and their metabolites.This study highlights the prognostic potential of intratumoral microbiota in predicting conversion therapy effectiveness in HCC.