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

作者：Kunling Chen, Huolun Feng, Yujie Zhang, Jingyuan Pei, Yuyan Xu, Xiangxu Wei, Zhuohao Chen, Zhoubin Feng, Lei Cai, Yong Li, Liang Zhao, Mingxin Pan · 发表于：Cancer Research · 年份：2025 · DOI：10.1158/0008-5472.can-24-4323 · 被引用次数：9 · 研究领域：Immune cells in cancer、Chemokine receptors and signaling、Angiogenesis and VEGF in Cancer

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. In this study, we aimed to identify potential therapeutic targets for remodeling aberrant tumor vasculature by analyzing CTCs from patients with early-stage HCC. 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, whereas 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 IL24 secretion. Pharmacologic intervention using sitagliptin, a DPP4 inhibitor, effectively stabilized tumor vasculature by preventing CCL16 degradation. Importantly, therapeutically elevating CCL16 levels combined with anti-PD-1 antibody administration synergistically enhanced vascular normalization and improved antitumor immunity in HCC models, suppressing tumor growth. These findings establish CCL16 as a critical regulator of vascular-immune cross-talk and propose DPP4 inhibition as a promising therapeutic strategy for treatin...