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

Hepatocellular carcinoma (HCC) is characterized by aberrant tumor vasculature and an immunosuppressive tumor microenvironment (TME), both of which compromise immunotherapy efficacy while promoting circulating tumor cell (CTC) dissemination and immune escape. Here, we aimed to identify potential therapeutic targets for remodeling aberrant tumor vasculature by analyzing CTCs from early-stage HCC patients. HCC tissue samples derived from patients with elevated CTC counts demonstrated significant CCL16 downregulation accompanied by vascular structural abnormalities and an immunosuppressive TME. CCL16 deficiency in murine models exacerbated both vascular dysfunction and immunosuppressive TME formation, while CCL16 overexpression mediated vascular normalization and promoted immune cell infiltration. Mechanistically, CCL16 interacted with ICAM-1 receptor on tumor-associated macrophages, triggering JAK2-STAT6 pathway activation and subsequent IL-24 secretion. Pharmacological intervention using sitagliptin, a DPP4 inhibitor, effectively stabilized tumor vasculature by preventing CCL16 degradation. Importantly, therapeutically elevating CCL16 levels combined with anti-PD1 antibody administration synergistically enhanced vascular normalization and improved anti-tumor immunity in HCC models, suppressing tumor growth. These findings establish CCL16 as a critical regulator of vascular-immune crosstalk and propose DPP4 inhibition as a promising therapeutic strategy for treating HCC.