In EGFR-dysregulated ESCC, we show reduced IGFBP3 with activation of IGF1R and functional effects of IGFBP3 on EGFR TKi responses which support further investigation of IGFBP3/pIGF1R levels in tissue samples from ESCC patients receiving EGFR-targeted therapy. Here, IGFBP3 is linked to esophageal squamous cell carcinoma.