Blood Lead Levels and Mortality Risk in Cancer Patients: A Prospective Cohort Study with Mediation and Pan-Cancer Pathway Analysis.

Blood lead levels were associated with increased mortality in cancer patients, with mediation analyses suggesting a partial role of oxidative stress and inflammation, and heterogeneity across cancer types linked to Hallmark pathway activity. We analyzed 2,689 cancer patients from NHANES (1999-2016) using Cox regression, restricted cubic spline, and mediation analyses. Over 22,151.5 person-years, 983 deaths occurred. Compared with the lowest quartile, the highest blood lead quartile was associated with increased all-cause mortality (HR = 2.44; 95% CI: 1.79-3.34) and cancer mortality (HR = 2.34; 95% CI: 1.20-4.46). Lipid-adjusted inflammation indicators-including uric acid-to-high-density lipoprotein ratio (UHR), monocyte-to-lymphocyte ratio (MLR), and systemic inflammatory response index (SIRI)-mediated 4.51-5.72% of the association, supporting partial mediation through oxidative stress and inflammation. The effect varied by cancer type and correlated with TCGA Hallmark pathway activities, including KRAS signaling (ρ = -0.95) and xenobiotic metabolism (ρ = 0.79), suggesting that molecular context modulates lead toxicity.