Exogenous Epstein-Barr virus nuclear antigen 1 induces ADAR1-driven tumor resistance against immunotherapy.

Immune checkpoint blockade (ICB) therapy continues to face limitations due to tumor resistance linked to suppressed interferon (IFN) signaling. This suppression can be attributed to multiple mechanisms, among which viral pathogens represent a compelling though not yet fully elucidated factor. Here, we demonstrate that exogenous Epstein-Barr virus-encoded EBNA1 drives immunosuppression via enhanced RNA-editing enzyme ADAR1-mediated RNA editing. Comparative tumor model analyses revealed that EBNA1 overexpression reduced CD8(+) T-cell infiltration, inhibited IFN responses, polarized macrophages toward the M2 phenotype, and accelerated tumor growth. Mechanistically, EBNA1 forms a trimeric complex with insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) and eukaryotic translation initiation factor 4G1 (EIF4G1), enhancing ADAR1 translation. Elevated ADAR1 further increased A-to-I editing of dsRNA, particularly within SINE elements near IFN-associated genes. This editing masked immunostimulatory signals, impairing RNA sensor activation and blunting IFN pathways. Notably, combining the EBNA1-targeting PROTAC degrader EP-1215 with anti-PD-1 effectively restored IFN signaling, enhanced T-cell infiltration, and suppressed EBNA1(+) tumors in humanized mice. This viral exploitation of RNA editing suggests that targeting EBNA1 could be a strategy to convert "cold" tumors into "hot" targets amenable to ICB therapy.