Here, we conclude that Tan exerts anti-migration and anti-invasion effects in ESCC cells by down-regulating GPNMB by suppressing GLI2-mediated GPNMB transcription, providing a new understanding of the tumor-inhibitory mechanism of Tan and the basis for the development of Tan as a therapeutic agent against ESCC. Here, GLI2 is linked to esophageal squamous cell carcinoma.