Characterized by a median survival ranging from 5 to 59 months and accounting for 70% of adult primary central nervous system tumors, glioma has been regarded as the most deadly brain malignancy that is essentially incurable [1, 2]. Currently, TMZ is widely used in glioma treatment and has been proved to benefits patients [3, 4]. Unfortunately, drug resistance restricts the clinical application of TMZ and therefore contributes to the dismal outcome of glioma patient [5, 6]. This challenging problem attributes to multitudes of aberrant molecular changes, such as MGMT promoter methylation, α5β1 integrin expression, sonic hedgehog and notch pathway activation [7–10]. However, none of them has been successfully translated into clinical application and resultantly improved TMZ efficacy [11–14]. Thus, comprehensive understanding of TMZ resistance in glioma is urgently needed.