In summary, we identified a key regulatory METTL14‐miR‐99a‐5p‐TRIB2 feedback circuit that epigenetically represses p21 through Akt/mTOR/S6K1/HDAC2 to promote cancer stemness and radioresistance in ESCC (Figure 8H). Here, HDAC2 is linked to esophageal squamous cell carcinoma.