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Objective <p>Hepatocellular carcinoma (HCC) is often detected at an advanced stage, limiting treatment options, while conversion therapy improves surgical eligibility and survival. Given that intratumoral microbiota influences the tumor microenvironment, this study aimed to address the following research question: how does intratumoral microbiota change after conversion therapy and correlate with treatment efficacy in patients with initially unresectable HCC (uHCC)?</p> Methods <p>This study (NCT06365034) enrolled patients with uHCC who received dual or triple-modality conversion therapy (immune checkpoint inhibitors [ICIs], tyrosine kinase inhibitors [TKIs], transarterial chemoembolization [TACE]/hepatic arterial infusion chemotherapy [HAIC]). Efficacy indicators (conversion rate, objective response rate [ORR], disease control rate [DCR], R0 resection rate) and safety were evaluated. Tumor tissues were stratified into pMajR and pMinR groups based on pathological response. Subsequent analyses included microbial profiling, Wilcoxon test, principal coordinate analysis (PCoA), Linear Discriminant Analysis Effect Size (LEfSe), and PICRUSt2 functional prediction.</p> Results <p>The conversion rate was 38.1%, ORR 44.4%, DCR 90.1%, and radical&#xa0;(R0) resection rate 100%, with a favorable safety profile. The pMinR group exhibited higher α-diversity (<i>p</i> &lt; 0.05) and distinct β-diversity, with enrichment of <i>Acidobacteriota/Chloroflexi</i> at the phylum level and <i>Halomonas/Arthrobacter</i> at the genus level. The pMajR group was dominated by <i>Proteobacteria/Bacteroidetes</i>, with elevated abundances of <i>Escherichia-Shigella</i> and <i>Limosilactobacillus</i>. LEfSe confirmed differential taxa with a Linear Discriminant Analysis (LDA) score &gt; 3.0: the pMinR group was enriched in methane metabolism and cofactor biosynthesis pathways, while the pMajR group showed enhanced fatty acid synthesis.</p> Conclusion <p>Intratumoral microbiota and their metabolic differences may influence the efficacy of conversion therapy, highlighting the potential of microbiota as a prognostic biomarker for predicting treatment outcomes in HCC.</p>

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Therapeutic response-driven discrepancies in intratumoral microbiota composition of hepatocellular carcinoma following conversion therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月8日

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  • Lin Ma,
  • Jiamei Xu,
  • Fuhai Wang,
  • Zongzhen Xu,
  • Feng Liu,
  • Tao Li,
  • Xiaolin Liu,
  • Beibei Yin,
  • Junjuan Xiao,
  • Hu Tian,
  • Ziqiang Li,
  • Chang Liu,
  • Jing Liang

摘要

Objective

Hepatocellular carcinoma (HCC) is often detected at an advanced stage, limiting treatment options, while conversion therapy improves surgical eligibility and survival. Given that intratumoral microbiota influences the tumor microenvironment, this study aimed to address the following research question: how does intratumoral microbiota change after conversion therapy and correlate with treatment efficacy in patients with initially unresectable HCC (uHCC)?

Methods

This study (NCT06365034) enrolled patients with uHCC who received dual or triple-modality conversion therapy (immune checkpoint inhibitors [ICIs], tyrosine kinase inhibitors [TKIs], transarterial chemoembolization [TACE]/hepatic arterial infusion chemotherapy [HAIC]). Efficacy indicators (conversion rate, objective response rate [ORR], disease control rate [DCR], R0 resection rate) and safety were evaluated. Tumor tissues were stratified into pMajR and pMinR groups based on pathological response. Subsequent analyses included microbial profiling, Wilcoxon test, principal coordinate analysis (PCoA), Linear Discriminant Analysis Effect Size (LEfSe), and PICRUSt2 functional prediction.

Results

The conversion rate was 38.1%, ORR 44.4%, DCR 90.1%, and radical (R0) resection rate 100%, with a favorable safety profile. The pMinR group exhibited higher α-diversity (p < 0.05) and distinct β-diversity, with enrichment of Acidobacteriota/Chloroflexi at the phylum level and Halomonas/Arthrobacter at the genus level. The pMajR group was dominated by Proteobacteria/Bacteroidetes, with elevated abundances of Escherichia-Shigella and Limosilactobacillus. LEfSe confirmed differential taxa with a Linear Discriminant Analysis (LDA) score > 3.0: the pMinR group was enriched in methane metabolism and cofactor biosynthesis pathways, while the pMajR group showed enhanced fatty acid synthesis.

Conclusion

Intratumoral microbiota and their metabolic differences may influence the efficacy of conversion therapy, highlighting the potential of microbiota as a prognostic biomarker for predicting treatment outcomes in HCC.