CRELD2, induced by the PERK-ATF4 pathway under ER stress, promotes localization of APMAP on the cell membrane, which subsequently triggers activation of TGF-β/SMAD and NF-κB signaling pathway, ultimately driving epithelial-mesenchymal transition and malignant progression of ESCC cells, and CRELD2 may serve as a promising therapeutic target for ESCC. Here, APMAP is linked to esophageal squamous cell carcinoma.