Collectively, this study presented comprehensive proteomic characterization of EESCC and EDAC at multi-omics level, and revealed the functional pathways of cell cycle in EESCC, the positive impacts of apoptosis, and metabolic processes in EDAC, and further demonstrated the potential co-functions of RB1 and EGFR in ESCC, and the key role of MTOR at the protein and phosphoprotein levels in EDAC. This evidence concerns the gene EGFR and esophageal squamous cell carcinoma.