In patients with esophageal squamous cell carcinoma, elevated tumor creatine levels combined with reduced hexokinase 3 (HK3) expression are associated with increased infiltration of M2-like tumor-associated macrophages and decreased cytotoxic immune cells, which correlates with significantly worse overall and progression-free survival.

When tumor cells accumulate creatine and lack HK3, macrophages inside the tumor switch to a healing mode that suppresses immune attacks. This happens because the macrophages stop using sugar for energy and instead use creatine to produce molecules that reduce harmful chemicals in the cell. This change turns off immune-stimulating signals and turns on signals that recruit immune cells that protect the tumor. These protective cells then block cancer-fighting cells from entering and killing the tumor, allowing it to grow and spread.