EBV-LMP1 stabilizes circadian CRY2 to drive immune escape and chemoresistance in nasopharyngeal carcinoma

The circadian rhythm is a fundamental biological phenomenon regulated by the clock gene family. Disruption of clock genes has been linked to various diseases, including cancer. Cryptochrome 2 (CRY2), a core circadian component, plays a role in tumorigenesis, yet its function in nasopharyngeal carcinoma (NPC) remains unclear. Epstein-Barr virus (EBV) infection is a key oncogenic factor in NPC, with latent membrane protein 1 (LMP1) being one of EBV-encoded principal oncoproteins. In the present study, we demonstrate that CRY2 mediates LMP1-induced proliferation, immune escape, and chemoresistance in NPC cells. Mechanistically, LMP1 enhances CRY2 stability by regulating phosphorylation-ubiquitination cascades and disrupting CRY2-FBXL3 interactions. CRY2 activates STAT3 to upregulate PD-L1, suppressing T-cell antitumor activity. Our findings elucidate the molecular link between EBV and circadian clock genes and identify the EBV-LMP1/CRY2 axis as a novel oncogenic pathway in NPC progression, highlighting CRY2 as a potential therapeutic target in EBV-associated cancers.