Importantly, the diagnostic performance of the combination of DKK‐1 and DKK‐1 autoantibodies persisted in early ESCC patients (AUC 0.780, 95% CI, 0.699–0.862, 50.0% sensitivity, and 90.7% specificity in the training cohort; AUC 0.745, 95% CI, 0.626–0.865, 53.8% sensitivity, and 84.9% specificity in the validation cohort). Here, DKK1 is linked to esophageal squamous cell carcinoma.