Hyperglycemia is common in patients with bladder cancer and has been implicated in disease progression, yet the molecular link between a high-glucose milieu and tumor aggressiveness remains poorly defined. Here we identify a noncanonical, nuclear role of hexokinase 2 (HK2) that couples systemic hyperglycemia to MYC-driven glycolysis and stemness in bladder cancer. High glucose promotes nuclear translocation of HK2, where HK2 directly binds the central region of MYC to form a functional transcrip...