Overall, our data support the following conclusions: first, RAP80 is a novel and independent biomarker for predicting the development of ESCC; second, targeting RAP80 is a promising way for ESCC patients’ therapy; third, combination application of RAP80 inhibitors and ATM inhibitors or USP13 inhibitors will remarkably increase the therapeutic opportunities for ESCC patients in the future. This evidence concerns the gene ATM and esophageal squamous cell carcinoma.