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

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.