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

Zhu-Long Hu, Zi-Qian Li, Yu Wang, Yi-Ling Luo, Wan-Ping Guo, Ning Meng, Guo-Long Bu, Le-Le Zhang, Shu-Xin Li, Xiang-Wei Kong, Xin-Yan Fang, Qiao-Li Wang, Run-Kun Han, Zheng Zhao, Ge-Xin Zhao, Zi-Ying Jiang, Run-Xian Jin, Mu-Sheng Zeng () and Qian Zhong ()
Additional contact information
Zhu-Long Hu: Sun Yat-sen University Cancer Center
Zi-Qian Li: Sun Yat-sen University Cancer Center
Yu Wang: Sun Yat-sen University Cancer Center
Yi-Ling Luo: Sun Yat-sen University Cancer Center
Wan-Ping Guo: Sun Yat-sen University Cancer Center
Ning Meng: Sun Yat-sen University Cancer Center
Guo-Long Bu: Sun Yat-sen University Cancer Center
Le-Le Zhang: Sun Yat-sen University Cancer Center
Shu-Xin Li: Sun Yat-sen University Cancer Center
Xiang-Wei Kong: Sun Yat-sen University Cancer Center
Xin-Yan Fang: Southern University of Science and Technology
Qiao-Li Wang: Sun Yat-sen University Cancer Center
Run-Kun Han: Sun Yat-sen University Cancer Center
Zheng Zhao: Sun Yat-sen University Cancer Center
Ge-Xin Zhao: Sun Yat-sen University Cancer Center
Zi-Ying Jiang: Sun Yat-sen University Cancer Center
Run-Xian Jin: Sun Yat-sen University
Mu-Sheng Zeng: Sun Yat-sen University Cancer Center
Qian Zhong: Sun Yat-sen University Cancer Center

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-64037-2

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