As highlighted by previous studies42 that a complex and intertwined network of multiple molecular mechanisms may together determine the therapeutic resistance of GBMs, our bioinformatic analyses showed that the enhanced TMZ resistance observed in high‐risk tumors may be partially attributable to the high enrichment of various cancer‐promoting or therapy‐resistant signatures involving in DNA damage response, energy metabolism, NF‐kB activation, ECM remodeling, and tumor immunity, as well as an increased abundance of immunosuppressive cells (e.g., Treg and MDSCs). The gene discussed is NFKB1; the disease is cancer.