We found that upregulated ESCC-derived EVs-miR-21-5p activated M0 macrophages to M2 macrophages through the PI3K/AKT/STAT6 pathway, which in turn resulted in high-level TGF-β1 secretion by M2 macrophages and changes of expression of EMT-associated genes in esophageal cancer cells via TGF-β/Smad2 signaling. Here, SMAD2 is linked to esophageal cancer.