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Background <p>Vessels encapsulating tumor clusters (VETC), an aggressive pathological pattern in hepatocellular carcinoma (HCC), is associated with unfavorable clinical outcomes. However, its role in first-line systemic therapies—immune checkpoint inhibitors alone (ICI-alone), tyrosine kinase inhibitors (TKIs) alone, or ICIs-based combinations (ICI-combo)—remains largely unexplored. This study aimed to compare therapy efficacy in unresectable HCC (uHCC) stratified by VETC.</p> Methods <p>A retrospective analysis of 111 uHCC patients (ICI-alone, <i>n</i> = 34; TKIs, <i>n</i> = 24; ICI-combo, <i>n</i> = 53) used pooled data from 19 prospective studies (2017–2024). Objective response rate (ORR), investigator-assessed progression-free survival (PFS), overall survival (OS), and pathological characteristics were investigated. Tumor immune microenvironment was compared between the VETC and non-VETC by immunohistochemistry and transcriptome sequencing.</p> Results <p>With a median follow-up of 47.9&#xa0;months, ICI-combo cohort demonstrated significantly superior ORR (49.1% vs. 20.6% [ICI-alone] vs. 16.7% [TKIs], <i>P</i> = 0.003) and mPFS (8.57 vs. 2.10 vs. 3.97&#xa0;months, <i>P</i> = 0.005), though no significant difference in OS was observed (median, 19.27 vs. 12.87 vs. 13.90&#xa0;months, <i>P</i> = 0.070). VETC-positive patients receiving ICI-alone had markedly inferior outcomes (DCR, 9.1%; mPFS, 1.63&#xa0;months; mOS, 3.47&#xa0;months) compared to those receiving TKIs or ICI-combo (<i>P</i> &lt; 0.05). Multivariate analysis confirmed VETC as an independent negative OS predictor in the ICI-alone cohort (HR = 3.42, <i>P</i> = 0.013). VETC tumors exhibited an immunosuppressive microenvironment (reduced CD8<sup>+</sup> T/CD20<sup>+</sup> B-cell infiltration and M2-like macrophage dominance), corroborated by transcriptomic downregulation of T/B cells and M1 macrophage-related genes.</p> Conclusions <p>VETC, characterized by reduced immune infiltration, is a negative predictor of first-line ICIs alone in uHCC, guiding personalized treatment selection in uHCC.</p>

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The vessels encapsulating tumor clusters (VETC) pattern is a negative predictor for first-line immune checkpoint inhibitors alone in unresectable hepatocellular carcinoma

  • 期刊论文

  • 发表日期：

    2026年4月24日

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  • Chunyu Lin,
  • Shuai Kang,
  • Jing Zhang,
  • Wenxuan Yu,
  • Xiaoqun Wang,
  • Xiangqi Huang,
  • Qinghua Cao,
  • Fang Liu

摘要

Background

Vessels encapsulating tumor clusters (VETC), an aggressive pathological pattern in hepatocellular carcinoma (HCC), is associated with unfavorable clinical outcomes. However, its role in first-line systemic therapies—immune checkpoint inhibitors alone (ICI-alone), tyrosine kinase inhibitors (TKIs) alone, or ICIs-based combinations (ICI-combo)—remains largely unexplored. This study aimed to compare therapy efficacy in unresectable HCC (uHCC) stratified by VETC.

Methods

A retrospective analysis of 111 uHCC patients (ICI-alone, n = 34; TKIs, n = 24; ICI-combo, n = 53) used pooled data from 19 prospective studies (2017–2024). Objective response rate (ORR), investigator-assessed progression-free survival (PFS), overall survival (OS), and pathological characteristics were investigated. Tumor immune microenvironment was compared between the VETC and non-VETC by immunohistochemistry and transcriptome sequencing.

Results

With a median follow-up of 47.9 months, ICI-combo cohort demonstrated significantly superior ORR (49.1% vs. 20.6% [ICI-alone] vs. 16.7% [TKIs], P = 0.003) and mPFS (8.57 vs. 2.10 vs. 3.97 months, P = 0.005), though no significant difference in OS was observed (median, 19.27 vs. 12.87 vs. 13.90 months, P = 0.070). VETC-positive patients receiving ICI-alone had markedly inferior outcomes (DCR, 9.1%; mPFS, 1.63 months; mOS, 3.47 months) compared to those receiving TKIs or ICI-combo (P < 0.05). Multivariate analysis confirmed VETC as an independent negative OS predictor in the ICI-alone cohort (HR = 3.42, P = 0.013). VETC tumors exhibited an immunosuppressive microenvironment (reduced CD8+ T/CD20+ B-cell infiltration and M2-like macrophage dominance), corroborated by transcriptomic downregulation of T/B cells and M1 macrophage-related genes.

Conclusions

VETC, characterized by reduced immune infiltration, is a negative predictor of first-line ICIs alone in uHCC, guiding personalized treatment selection in uHCC.