Systemic Inflammation Mediates the Association Between Plasma Epstein–Barr Virus DNA and Mortality in Metastatic Nasopharyngeal Carcinoma

ABSTRACT We aimed to comprehensively evaluate the associations of a broad panel of systemic inflammation‐related biomarkers with overall survival (OS) in metastatic nasopharyngeal carcinoma (mNPC) and to assess whether these signatures mediate the adverse impact of high EBV DNA burden on long‐term outcomes. This study included 1847 patients with mNPC treated at Sun Yat‐sen University Cancer Center between 2016 and 2022. Multivariable Cox proportional hazards models, restricted cubic spline (RCS) models, and time‐dependent receiver operating characteristic (ROC) curve analyses were used to evaluate associations of inflammation‐related indices with OS. Exploratory mediation analyses quantified the extent to which biomarkers partially mediated the association between plasma EBV DNA burden and mortality risk. Mean follow‐up was 45.4 months; 713 (38.6%) deaths occurred. Plasma EBV DNA showed stable discrimination (AUCs of 0.63, 0.62, and 0.61 for 1‐, 3‐, and 5‐year OS). After full adjustment, CALLY and LCR were protective, whereas CAR, NAR, SIRI, IBI, MLR, NC, PC, GPS, mGPS, and LCS were adverse. CAR, CALLY, LCR, IBI, and NC showed the highest discrimination (1‐year AUCs, 0.65–0.66). Mediation analyses indicated that MLR, SIRI, CALLY, and NC accounted for 7.6%–9.6% of the EBV DNA load‐mortality association. Elevated pretreatment EBV DNA was associated with a coordinated systemic inflammatory profile and worse OS in mNPC. Selected inflammatory markers statistically accounted for a modest proportion of the observed association between EBV DNA burden and mortality. Integrating EBV DNA with inflammatory profiles may improve risk stratification and guide intensified surveillance, earlier assessment, and risk‐adapted therapy.