Elevated HOXD‐AS2 expression promoted progression and negatively correlated with prognosis of glioma; HOXD‐AS2 attenuated temozolomide sensitivity in vitro and in vivo; The clinical case also showed that lower HOXD‐AS2 sensitized glioblastoma to temozolomide; STAT3‐induced HOXD‐AS2 could interact with IGF2BP2 protein to form a complex and sequentially upregulate STAT3 signaling, thus forming a positive feedback loop regulating TMZ sensitivity in glioblastoma. The gene discussed is STAT3; the disease is central nervous system cancer.