Both molecules show synergistic effects on HNSCC in vitro and in vivo. They also synergistically promote cell cycle arrest. By inhibiting the mTOR and stat3 pathways, Metformin modulates the profiles of the SASP induced by the CDK4/6 inhibitor. Metformin blocks the SASP-induced stemness caused by a CDK4/6 inhibitor, and the blockade of the IL6-stat3 axis by Metformin is associated with stemness inhibition. Here, IL6 is linked to head and neck squamous cell carcinoma.