Vessels encapsulating tumor clusters is associated with impaired efficacy of adjuvant immunotherapy in resected hepatocellular carcinoma

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INTRODUCTION: Aggressive pathologic features are closely associated with early recurrence of hepatocellular carcinoma (HCC), and the association between vessels encapsulating tumor clusters (VETC) and poor prognosis has received increasing attention. OBJECTIVES: This study aimed to investigate the role of adjuvant Sintilimab (AS) with or without Lenvatinib (ASL) compared to active monitoring (AM) in high-risk HCC, with emphasis on VETC-positive subtypes. METHODS: Patients identified as being at high risk for recurrence and who had undergone either AM, AS, or ASL were retrospectively enrolled from four medical centers. Propensity score matching (PSM) was adopted to minimize bias. Digital spatial profiling (DSP) and multiplex immunofluorescence (mIF) were employed to elucidate the molecular underpinnings of VETC-positive HCC. RESULTS: This study included 620 patients with a median follow-up of 46.9 months. After PSM, 135 patients were allocated to each cohort. Both the AS and ASL regimens significantly prolonged median disease-free survival compared to AM (26.0 and 59.2 months vs. 12.2 months, respectively; p < 0.001). Critically, subgroup analysis revealed that the benefit of AS was absent in VETC-positive HCC (p = 0.681), whereas ASL demonstrated a substantial reduction in recurrence (p = 0.001). This specific efficacy of Lenvatinib against VETC-positive HCC was further corroborated by data from first-line treatment for recurrent disease and an independent neoadjuvant therapy cohort. Mechanistically, DSP revealed that VETC-positive tumors possess an immunosuppressive microenvironment, characterized by downregulated antigen presentation and impoverished CD8+ T cell infiltration. This immune contexture was validated by mIF, which confirmed sparse CD8+ T cells alongside enriched CD4+ and regulatory T cells in VETC-positive HCC. CONCLUSIONS: This study validates VETC-positive HCC as a distinct entity with a high risk of postoperative recurrence and validates the combination of PD-1 inhibitors with Lenvatinib as its preferred therapeutic strategy.