A comprehensive scRNA sequencing and ST study of 79 multistage esophageal lesions from 29 patients with ESCC revealed a gradual and significant loss of ANXA1 expression in epithelial cells due to its transcription factor KLF4 suppression along the lesion progression and underscores ANxA1/FPR2 signaling as an important crosstalk mechanism between epithelium and fibroblasts in promoting ESCC. Here, KLF4 is linked to esophageal squamous cell carcinoma.