TGF-β binds to its receptor TGFβR1/2 on the cell membrane and induces a signaling cascade by phosphorylating Smad2/3 [28]. The classical Smad2/3 pathway was abnormally activated in ESCC cells when treated with M2-CM (Fig. 3A). The gene discussed is TGFB1; the disease is esophageal squamous cell carcinoma.