IFN-γ-mediated suppression of ANGPT2-Tie2 in endothelial cells facilitates tumor vascular normalization during immunotherapy

作者：Zihao Cai, Kelin Meng, Taiyan Yu, Yu Xi, Zhiwei Yuan, Xue Wang, Congjian Wang, Lequn Li, Xiangning Fu · 发表于：Frontiers in Immunology · 年份：2025 · DOI：10.3389/fimmu.2025.1551322 · 被引用次数：16 · 研究领域：Angiogenesis and VEGF in Cancer、Lipid metabolism and disorders、Cancer, Hypoxia, and Metabolism

Introduction Tumor angiogenesis is a critical biological hallmark of cancer, which involves multiple molecularly regulated signaling pathways, including the angiopoietin (ANGPT)-Tie2 and the vascular endothelial growth factor (VEGF) signaling pathways. Despite initial optimism, targeting tumor angiogenesis in the treatment of lung adenocarcinoma (LUAD) has been unsatisfactory. Currently, monotherapy with PD-1/PD-L1 inhibitors, or their combination with bevacizumab, is considered the standard therapeutic approach for LUAD. Recent studies have shown that immunotherapy suppresses tumor angiogenesis and facilitates vascular normalization. However, whether and how anti-PD-L1 therapy influences tumor vasculature remains unclear. Methods To investigate the impact of immunotherapy on the vasculature of LUAD, a mouse model of lung adenocarcinoma was established by subcutaneous implantation of Lewis lung carcinoma cells in vivo . The effects of different treatments on microvessel density and pericyte coverage were explored, and the expression of angiogenesis-related factors was analyzed. Furthermore, to explore the molecular mechanisms through which IFN-γ regulates tumor blood vessels during immunotherapy, we elucidated the specific mechanisms in vitro by means of techniques such as siRNA, ChIP, RT-qPCR, Western blot, and immunofluorescence. Finally, the effects of IFN-γ on the proliferation, migration, and angiogenic function of endothelial cells (ECs) were evaluated through CCK-8, Tr...