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

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