In esophageal squamous cell carcinoma, low expression of hexokinase 3 (HK3) is associated with increased immune cell infiltration and improved survival, and HK3 deficiency synergizes with elevated creatine levels to promote M2 macrophage polarization and tumor progression.

When hexokinase 3 is low and creatine is high, immune cells called macrophages switch from fighting cancer to helping it grow. This happens because the macrophages stop using sugar for energy and instead use creatine to produce a molecule that reduces harmful chemicals inside the cell. This change turns off signals that make macrophages attack tumors and turns on signals that make them suppress the immune system, allowing the tumor to grow unchecked.