2. Academic Validation
  3. Extracellular vesicles derived EBV tegument protein BRRF2 suppresses cGAS phase separation to promote anti-viral innate immune evasion

Extracellular vesicles derived EBV tegument protein BRRF2 suppresses cGAS phase separation to promote anti-viral innate immune evasion

  • Nat Commun. 2025 Oct 10;16(1):9015. doi: 10.1038/s41467-025-64037-2.
Zhu-Long Hu # 1 2,  Zi-Qian Li # 1,  Yu Wang # 1,  Yi-Ling Luo 1,  Wan-Ping Guo 1,  Ning Meng 1,  Guo-Long Bu 1,  Le-Le Zhang 1,  Shu-Xin Li 1,  Xiang-Wei Kong 1 3,  Xin-Yan Fang 4,  Qiao-Li Wang 1,  Run-Kun Han 1 5,  Zheng Zhao 1 6,  Ge-Xin Zhao 1,  Zi-Ying Jiang 1,  Run-Xian Jin 7,  Mu-Sheng Zeng 8,  Qian Zhong 9
Affiliations

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, P. R. China.
  • 2 State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Hubei University, Wuhan, P. R. China.
  • 3 Department of Otorhinolaryngology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P. R. China.
  • 4 Southern University of Science and Technology, Shenzhen, P. R. China.
  • 5 Department of Clinical Laboratory, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, P. R. China.
  • 6 Department of Head and Neck Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, P. R. China.
  • 7 Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, P. R. China.
  • 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, P. R. China. 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, P. R. China. zhongqian@sysucc.org.cn.
  • # Contributed equally.
PMID: 41073405 DOI: 10.1038/s41467-025-64037-2
Abstract

Viral strategies to antagonize the robust host innate immune response have a major function in the pathogenicity of viral Infection and virus-associated cancers. Epstein-Barr virus (EBV) Infection causes infectious mononucleosis (IM) and several human cancers. While latent EBV can reactivate in some nasopharyngeal carcinoma (NPC) cells, the impact of EBV reactivation on the anti-viral innate immune and immunotherapy response of NPC patients remains incompletely understood. Here, we reveal the function of the EBV-encoded BRRF2 protein as a pivotal regulator of the host immune system. We show that BRRF2, which is secreted via extracellular vesicles (EVs) from NPC cells undergoing EBV reactivation, specifically targets macrophages. It disrupts the Cyclic GMP-AMP Synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway, which is crucial for innate immunity. BRRF2 inhibits the enzymatic activity of cGAS by interfering with the interaction of cGAS with dsDNA and reducing cGAS-DNA phase separation. Notably, our research shows a marked increase in the levels of BRRF2+ EVs in the bloodstream of NPC patients, which is closely associated with a diminished response to immunotherapy. By identifying BRRF2 as a potential biomarker for immunotherapy resistance, our findings provide deeper insight into the contribution of EBV to viral immunology and suggest further avenues for therapeutic intervention to increase the efficacy of immunotherapy.

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