The CXCL10‐CXCR3 Axis Induces Tumor‐Associated Neutrophils to Interfere with CTLs‐Mediated Antitumor Activity in EBV‐Associated Epithelial Cancers
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.
Authors
- Jinqi You
- Yan Ren (ORCID: https://orcid.org/0000-0001-5993-9248)
- Mengjia Song (ORCID: https://orcid.org/0000-0002-6399-3412)
- Jian‐Chuan Xia (ORCID: https://orcid.org/0000-0002-1268-3967)
- Hao Chen (ORCID: https://orcid.org/0009-0009-2070-4666)
- Yong Tao (ORCID: https://orcid.org/0000-0002-1351-2094)
- Dijun Ouyang (ORCID: https://orcid.org/0009-0006-0735-2887)
- Jingjing Zhao (ORCID: https://orcid.org/0000-0002-5089-7608)
- Yuanyuan Liu
- Tong Xiang (ORCID: https://orcid.org/0000-0002-5286-587X)
- Qi-jing Wang (ORCID: https://orcid.org/0009-0000-1682-0378)
- Yong-qiang Li (ORCID: https://orcid.org/0009-0000-1827-6572)
- Yuanyuan Chen (ORCID: https://orcid.org/0000-0002-5358-9213)
- Qiuzhong Pan (ORCID: https://orcid.org/0000-0002-2145-535X)
- Jia He (ORCID: https://orcid.org/0009-0003-6163-9692)
- Songzuo Xie (ORCID: https://orcid.org/0009-0000-3266-1864)
- Si Li (ORCID: https://orcid.org/0000-0001-7997-0904)
- Yan Wang (ORCID: https://orcid.org/0000-0002-6108-2025)
- Lifeng Zhang (ORCID: https://orcid.org/0000-0001-6125-7502)
- Chi Xu
- Yingzi Li (ORCID: https://orcid.org/0000-0001-7507-9751)
- Qi Yang (ORCID: https://orcid.org/0000-0001-9607-9881)
- Xinyi Yang (ORCID: https://orcid.org/0000-0003-4453-1383)
- Desheng Weng
- Sisi Xie (ORCID: https://orcid.org/0009-0007-2369-6046)
Institutions
- Sun Yat-sen University (CN)
- Beike Biotechnology (China) (CN)
- Sun Yat-sen University Cancer Center (CN)
- Third Affiliated Hospital of Sun Yat-sen University (CN)
- Guangzhou Electronic Technology (China) (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-07-21
- DOI
- https://doi.org/10.1002/advs.202500950
- Citations
- 1
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.80
Funders
- National Natural Science Foundation of China
- Sun Yat-sen University
- Natural Science Foundation of Guangdong Province
- Fundamental Research Funds for the Central Universities
- Basic and Applied Basic Research Foundation of Guangdong Province