This study reveals that anti-angiogenic therapy synergizes with immune checkpoint blockade by inducing the formation of high endothelial venules (HEVs) through the non-canonical VEGFC–NF-κB pathway, thereby promoting tumor infiltration of CCR7+CD8+ T cells. These findings provide a novel mechanistic explanation and therapeutic target for improving immunotherapy response in liver cancer.
Literature Overview
The article titled 'Anti-angiogenic therapy combined with immune checkpoint blockade mediates CCR7+CD8+ T-cell entry into HCC through high endothelial venules,' published in Hepatology (Baltimore, Md.), systematically investigates the immunomodulatory mechanisms of anti-angiogenic drugs (AAD) combined with immune checkpoint blockade (ICB) in hepatocellular carcinoma (HCC). The study focuses on the formation of high endothelial venules (HEVs) and their role in T cell infiltration, revealing HEVs as critical gateways for immune cell entry into tumors. Using multi-omics analysis and spatial pathology techniques, the authors elucidate the molecular pathway by which VEGFC drives HEV formation and recruits CCR7+CD8+ T cells, offering new insights into overcoming the immunosuppressive tumor microenvironment in HCC.Background Knowledge
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death in China, and its immunosuppressive tumor microenvironment (TME) severely limits the efficacy of ICB therapies. Although the combination of anti-angiogenic therapy and ICB has shown clinical benefits, most patients still fail to achieve durable responses, primarily due to inefficient infiltration of effector T cells into tumor parenchyma. Abnormal vasculature traditionally leads to an 'immune-excluded' phenotype that hinders T cell migration. HEVs, specialized vascular structures, have been shown to mediate lymphocyte entry from blood into lymphoid tissues or tumors. However, the mechanisms underlying HEV formation in HCC and their functional role in regulating T cell subset infiltration remain unclear. This study addresses this knowledge gap by proposing that VEGFC may induce HEV formation via activation of the non-canonical NF-κB pathway, thereby promoting tumor homing of CCR7+CD8+ T cells, offering a potential intervention node to enhance combination therapy efficacy.
Research Methods and Experiments
The research team performed snRNA-seq to conduct single-cell transcriptomic analysis on HCC tumor tissues from patients who underwent surgery versus those treated with AAD+ICB, identifying enrichment of HEV endothelial cell subsets. Using multiplex immunohistochemistry (mIHC) and spatial analysis technologies, they confirmed a positive correlation between HEV density and CD3+ T cell infiltration, and found significant spatial co-localization between CCR7+CD8+ T cells and HEVs. In a Hepa1-6 orthotopic liver tumor mouse model, treatment with apatinib and anti-PD-1 antibody mimicked the clinical combination therapy and significantly increased both HEV numbers and T cell infiltration. A GFP+ lymphocyte transfer experiment directly demonstrated the HEV-dependent T cell entry mechanism. Furthermore, interventions using VEGFC stimulation and LTβR-Fc blockade revealed the critical role of the VEGFR3–LTβR–non-canonical NF-κB signaling axis in HEV formation.Key Conclusions and Perspectives
Research Significance and Prospects
This study provides a novel mechanistic perspective for HCC immunotherapy: by inducing HEV formation, tumor vascular immune phenotypes can be remodeled to promote functional CCR7+CD8+ T cell entry into tumors. This offers a combinatorial targeting strategy to overcome the limitations of ICB monotherapy, suggesting VEGFC agonists or LTβR agonists may enhance current therapeutic efficacy. Future efforts could explore drug development targeting HEVs, such as small molecules or antibodies promoting HEV differentiation. Additionally, HEV density may become a clinical monitoring metric for identifying patient populations most likely to benefit from combination therapy.
Conclusion
This study systematically reveals the molecular mechanism by which anti-angiogenic therapy combined with immune checkpoint blockade induces high endothelial venule (HEV) formation via the VEGFC–NF-κB non-canonical pathway, thereby promoting CCR7+CD8+ T cell entry into the HCC tumor microenvironment. This finding not only explains the intrinsic reasons for favorable responses to combination therapy in some patients but also provides a new strategy for improving the microenvironment of immunologically 'cold' tumors. From bench to bedside, targeting the HEV formation pathway is poised to become a key step in enhancing T cell infiltration and improving immunotherapy efficacy. Particularly in HCC—a highly prevalent and difficult-to-treat cancer—HEVs as potential prognostic biomarkers and therapeutic targets will advance the development of precision immunotherapy and lay the foundation for building a more effective liver cancer care system.
