SE usually recruits lineage‐specific TFs (SOX2, TP63, FOSL1, and others) and transcriptional co‐activators to cooperatively activate target gene transcription to drive cancer progression.[11, 12, 19, 20, 21] Our results identified SOX2 and SMAD3 as key TFs to bind LIF‐SE and transcriptionally activate LIF via recruitments of SE‐associated co‐activators like EP300 and BRD4 as transcriptional complexes. Here, SOX2 is linked to cancer.