Circulating cell-free Epstein-Barr virus DNA measurement for nasopharyngeal carcinoma: advancing towards ctDNA-guided, risk-adaptive individualized treatment.

Circulating tumor-derived DNA (ctDNA) has emerged as a pivotal tool for cancer screening, pre-treatment prognostic risk stratification, on-treatment response evaluation, and post-treatment recurrence surveillance. The pursuit of tumor-specific ctDNA biomarkers has been a long-standing and concerted effort in cancer research. Among these, cell-free Epstein-Barr virus (EBV) DNA (cfEBV DNA) has been recognized as a robust disease-specific biomarker for nasopharyngeal carcinoma (NPC) in endemic regions. EBV was the first DNA virus linked to human malignancies and is predominantly present in its latent form in NPC. For patients with NPC, cfEBV DNA released by dead tumor cells not only reflects tumor burden but is also associated with the host immune status and viral clearance capacity. More importantly, external stressors such as chemotherapy and radiotherapy can alter the infection status of EBV from latency to lytic phase, which may lead to increased viral DNA synthesis, as well as the expression of lytic-associated proteins. These treatment-induced changes can, in turn, impact the therapeutic efficacy of NPC. Owing to these unique properties, cfEBV DNA emerges as a promising biomarker for the longitudinal assessment of therapeutic response and clinical outcomes in NPC. This review summarizes recent advances in the application of cfEBV DNA for disease screening, prognostication, and surveillance, with particular emphasis on its serial tracing during treatment for real-time response evaluation and dynamic recurrence risk monitoring. We also discuss future perspectives on risk-adaptive, individualized treatment strategies of NPC guided by longitudinal cfEBV DNA monitoring during treatment.