Tumor-derived CCL16 Normalizes Tumor Vasculature through Macrophage ICAM-1 Receptor and Enhances Immunotherapy in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is characterized by aberrant vasculature and an immunosuppressive tumor microenvironment (TME), both of which impede effective immunotherapy and promote the dissemination of circulating tumor cells (CTC). This study investigates the role of liver-specific chemokine ligand 16 (CCL16) in modulating tumor vasculature and TME in HCC. Using CTC liquid biopsy and RNA sequencing, we demonstrated that patients with high CTC counts exhibited low CCL16 expression and abnormal vasculature in the TME. Furthermore, CCL16 deficiency reduced effector immune cell infiltration in murine models, whereas CCL16 overexpression rectified vascular abnormalities and enhanced immune cell infiltration. Mechanistically, CCL16 interacts with the ICAM-1 receptor, activating the JAK2-STAT6 pathway and promoting IL-24 secretion in tumor-associated macrophages. Additionally, sitagliptin corrected abnormal tumor vasculature by inhibiting CCL16 degradation. Increasing CCL16 levels, combined with anti-PD1 antibody, further improved tumor vascular normalization and immunotherapeutic efficacy in HCC. These findings identify CCL16 and DPP4 inhibitors as potential therapeutic targets for enhancing tumor vascular normalization, reversing inadequate immune cell infiltration, and improving immunotherapy outcomes in HCC.