Antiangiogenic therapy combined with immune checkpoint blockade mediates CCR7+CD8+ T-cell entry into HCC through high endothelial venules

Background & Aims: Hepatocellular carcinoma (HCC) remains a leading cause of cancer mortality in China. Anti-angiogenic drugs (AADs) plus immune checkpoint blockade (ICB) combination therapy shows considerable promise for HCC; however, its efficacy is hampered by immunosuppression within the tumor microenvironment. High endothelial venules (HEVs) facilitate lymphocyte migration and tumor infiltration. The aim was to study the formation, functional mechanisms, and clinical relevance of HEVs in the treatment of HCC with combination therapy. Approach & Results: Single-nucleus RNA sequencing, flow cytometry, and immunohistochemistry revealed increased HEV expression and higher CD3⁺ T-cell infiltration in HCC tissue after combination AAD and ICB therapy. Multiplex immunohistochemistry and spatial analysis demonstrated that CCR7⁺CD8⁺ T cells were spatially associated with HEVs. Pseudotime analysis of human T cells and treatment of Hepa1-6 orthotopic liver tumor mouse models with CCR7 + CD8 + T-cell transfusions were used to show that CCR7 + CD8 + T cells can differentiate into cytotoxic effector T cells. The same models demonstrated that combination therapy activated VEGFC and non-canonical NF-κB pathways, promoting HEV formation. Kaplan-Meier analysis revealed that high HEV density correlated with improved clinical response and prolonged survival. Conclusions: HEVs are pivotal in modulating immune activity within the HCC tumor microenvironment. Targeting the VEGFC–NF-κB (non- canonical)–HEV axis could be a promising therapeutic strategy to enhance antitumor immunity and improve outcomes in patients with HCC who are receiving combination AAD plus ICB therapy.