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Nasopharyngeal carcinoma (NPC) is an epithelial malignancy with a high prevalence in southern China and southeast Asia.1 In these endemic regions, NPC demonstrates an obligate, nearly ubiquitous association with Epstein-Barr virus (EBV) infection. The presence of EBV in virtually all NPC tumour cells provided the fundamental rationale for the development of EBV-based diagnostic biomarkers, such as plasma EBV DNA and EBV antibodies.2–5 A series of large-scale clinical trials have advanced the paradigms of NPC screening, demonstrating that population-level screening in endemic areas facilitates early-stage NPC detection, which can be translated into clear survival benefits.3 Despite these clinical advancements, the complex biology of EBV-associated NPC is not fully understood. There is a significant clinical paradox: while EBV establishes a lifelong, asymptomatic latent infection in over 90% of the global population, only a highly restricted subset of individuals develop EBV-associated NPC. This epidemiological discrepancy indicates that EBV infection alone may not sufficiently explain the occurrence of NPC, underscoring the potential contribution of genetic susceptibilities and environmental factors to the biological processes underlying the disease. Current evidence indicates the oncogenesis and disease severity of NPC is driven by a highly integrated network, including host genetic susceptibility (notably HLA polymorphisms),6 viral genomic variations,7 8 epigenetic modifications9 and complex intercellular crosstalk in the tumour microenvironment.10