SOX2/SMAD3 preferentially binds to LIF‐SE which recruits BRD4/EP300 to activate LIF transcription; LIF produced by cancer cells and CAFs activates LIFR/gp130‐STAT3 signaling which in turn promotes SOX2 transcription by STAT3 binding in its promoter region, thus forming a previously unknown feedback loop to augment LIF and facilitate stemness in HNSCC. Here, LIFR is linked to head and neck squamous cell carcinoma.