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

  • Adv Sci (Weinh). 2025 Jul 21:e00950. doi: 10.1002/advs.202500950.
Dijun Ouyang  1  2 ,  Tong Xiang  1  3 ,  Yuanyuan Chen  1  2 ,  Mengjia Song  1  4 ,  Jingjing Zhao  1  2 ,  Hao Chen  1  2 ,  Si Li  5 ,  Lifeng Zhang  5 ,  Chi Xu  6 ,  Yan Ren  6 ,  Yong Tao  6 ,  Qijing Wang  1  2 ,  Jia He  1  2 ,  Yongqiang Li  1  2 ,  Sisi Xie  6 ,  Yuanyuan Liu  1  2 ,  Yan Wang  7 ,  Xinyi Yang  1  2 ,  Jinqi You  1 ,  Songzuo Xie  1  8 ,  Yingzi Li  1  2 ,  Desheng Weng  1  2 ,  Qiuzhong Pan  1  2 ,  Qi Yang  1  9 ,  Jianchuan Xia  1  2
Affiliations
  • 1. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China.
  • 2. Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China.
  • 3. Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China.
  • 4. Department of Pediatric Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China.
  • 5. TCRCure Biological Technology Co., Ltd, Guangzhou, China.
  • 6. Knowcell Biotechnology Co., Ltd, Shenzhen, China.
  • 7. Department of Medical Oncology, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, China.
  • 8. Department of Nuclear Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
  • 9. Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
PMID: 40686457 DOI: 10.1002/advs.202500950
Abstract

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.

Keywords
EBV; EBVaGC; NPC; neutrophil extracellular traps; tumor‐associated neutrophils.
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