Interferon-responsive HEVs drive tumor tertiary lymphoid structure formation and predict immunotherapy response in nasopharyngeal carcinoma

Shang-Xin Liu; Tao-Wei Wu; Dong-Hua Luo; Le-Le Zhang; Lu Zhou; Yi-Ling Luo; Wen-Ting Du; Ting-Ting Huang; Sizun Jiang; Zhe Zhang; Ping Han; Mu-Sheng Zeng; Qian Zhong

doi:10.1016/j.xcrm.2025.102200

Interferon-responsive HEVs drive tumor tertiary lymphoid structure formation and predict immunotherapy response in nasopharyngeal carcinoma

Cell Rep Med. 2025 Jun 17:102200. doi: 10.1016/j.xcrm.2025.102200. Online ahead of print.

Authors

Shang-Xin Liu¹, Tao-Wei Wu², Dong-Hua Luo³, Le-Le Zhang¹, Lu Zhou⁴, Yi-Ling Luo¹, Wen-Ting Du¹, Ting-Ting Huang⁴, Sizun Jiang⁵, Zhe Zhang⁶, Ping Han⁷, Mu-Sheng Zeng⁸, Qian Zhong⁹

Affiliations

¹ State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China.
² Department of Otolaryngology-Head and Neck Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, P.R. China.
³ Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China.
⁴ Department of Otorhinolaryngology and Head and Neck Surgery, First Affiliated Hospital, Guangxi Medical University, Nanning 530021, P.R. China.
⁵ Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
⁶ Department of Otorhinolaryngology and Head and Neck Surgery, First Affiliated Hospital, Guangxi Medical University, Nanning 530021, P.R. China. Electronic address: zhangzhe1975@gmail.com.
⁷ Department of Otolaryngology-Head and Neck Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, P.R. China. Electronic address: hanping5@mail.sysu.edu.cn.
⁸ State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China; Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Guangzhou 510060, P.R. China. Electronic address: zengmsh@sysucc.org.cn.
⁹ State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China. Electronic address: zhongqian@sysucc.org.cn.

PMID: 40543508
DOI: 10.1016/j.xcrm.2025.102200

Abstract

The outcome of immune checkpoint blockade (ICB) therapy largely hinges on the antitumor immunity of tertiary lymphoid structures (TLSs), but drivers of tumor TLS formation remain exclusive. By integrating spatial transcriptomics and a pan-cancer single-cell atlas, we reveal the characteristics of TLSs in nasopharyngeal carcinoma (NPC) and identify a subset of interferon-responsive high endothelial venules (IFN-HEVs) that links to the emergence of tumor-specific chemokines, especially CXCL9. Functionally, CXCL9-secreting IFN-HEVs are associated with the recruitment of CXCR3⁺CD4⁺ T cells into TLSs. IFN-HEV-related phenotypes are strongly correlated with prolonged survival and enhanced ICB responsiveness. Leveraging these phenotypes, we develop a pretreatment CXCL9-TLS response-predictive scoring system (CTRscore), which robustly forecasts ICB therapeutic outcomes in three independent NPC cohorts. Our study provides biological and functional insights into the IFN-HEVs in tumor TLSs, highlighting their potential role in the development of biomarkers and predictors for the success of ICB therapy.

Keywords: CXCL9; high endothelial venules; immunotherapy; immunotherapy response; interferon; interferon-responsive high endothelial venules; nasopharyngeal carcinoma; prediction model; tertiary lymphoid structures.