EBV (LMP1) enhances cisplatin resistance by enhancing degradation of interferon regulatory factor 3.

EBV employs multiple strategies to subvert host innate immunity, including suppression of type I IFN signaling. However, the precise mechanism by which its latent oncoprotein LMP1 modulates this pathway in nasopharyngeal carcinoma (NPC) remains unclear. Here, we demonstrated that LMP1 enhances the interaction between interferon regulatory factor 3 (IRF3) and E3 ubiquitin ligase Ro52, which leads to the degradation of IRF3 protein. Low IRF3 expression correlates with poor prognosis in NPC patients. Notably, IRF3 may inhibit cell G1/S transition by directly inducing CDKN2C transcription, which suggests the direct effect as a moonlighting protein in regulating cell cycle. Cisplatin is an effective DNA-damaging anti-tumor agent which may activate type I IFNs-mediated anti-tumor immunity by stimulating the release of dsDNA. EBV (LMP1) inhibits cisplatin-activated type I IFN signaling by reducing IRF3 expression. The activation of IRF3 enhances the sensitivity of EBV (LMP1)-positive NPC cells to cisplatin in vitro and in vivo. These findings establish the LMP1-Ro52-IRF3 axis as a critical immune evasion mechanism that drives cisplatin resistance and suggest that targeting this axis represents a viable strategy to enhance chemotherapy efficacy in EBV-positive NPC.