Taken together, our study uncovers the function of TGFβ2 in ESCC metastasis, and establishes that imperatorin directly targets and represses transcriptional activity of CREB1 to inhibit TGFβ2 expression and the subsequent fibroblasts‐secreted CCL2, subsequently, not only inactivates ERK signaling to block cancer cell invasion, but also abrogates the paracrine effects of fibroblasts on tumor angiogenesis and metastasis (Figure 5K). Here, CCL2 is linked to esophageal squamous cell carcinoma.