The CXCL10‐CXCR3 Axis Induces Tumor‐Associated Neutrophils to Interfere with CTLs‐Mediated Antitumor Activity in EBV‐Associated Epithelial Cancers

作者：Dijun Ouyang, Tong Xiang, Yuanyuan Chen, Mengjia Song, Jingjing Zhao, Hao Chen, Si Li, Lifeng Zhang, Chi Xu, Yan Ren, Yong Tao, Qi-jing Wang, Jia He, Yong-qiang Li, Sisi Xie, Yuanyuan Liu, Yan Wang, Xinyi Yang, Jinqi You, Songzuo Xie, Yingzi Li, Desheng Weng, Qiuzhong Pan, Qi Yang, Jian‐Chuan Xia · 发表于：Advanced Science · 年份：2025 · DOI：10.1002/advs.202500950 · 被引用次数：6 · 研究领域：Immune cells in cancer、Neutrophil, Myeloperoxidase and Oxidative Mechanisms、Chemokine receptors and signaling

Although Epstein-Barr virus (EBV)-associated epithelial cancers are categorized as immunologically "hot" tumors, they have unsatisfactory responses to immunotherapy. Increasing evidence has shown that therapeutic failure is due to an immunosuppressive tumor microenvironment established by EBV. In this study, a negative correlation is found between the infiltration of neutrophils and that of cytotoxic T lymphocytes (CTLs) containing granzyme B in EBV-associated epithelial cancers. The CXCL10-CXCR3 axis in EBV-associated epithelial cancer cells controls the extrusion of neutrophil extracellular traps (NETs), which interferes with the antitumor activity of EBV antigen-specific T cells in vitro and in vivo. NETs are positively correlated with the number of dysfunctional CTLs in EBV-associated epithelial cancers, and are confirmed to be an independent prognostic factor for patients with EBV-associated epithelial cancers. In conclusion, these findings reveal a novel mechanism of immunosuppression of tumor-associated neutrophils (TANs) in EBV-associated epithelial cancers. Targeting NETs formation in TANs may be a potential strategy for improving the efficacy of immunotherapy against EBV-associated epithelial cancers.