Sodium-Glucose Cotransporter SGLT2 Supports Metabolic Fitness and Ferroptosis Resistance in CAR-T Cells to Enhance Activity Against Solid Tumors

Abstract Antitumor T-cell function is tightly coupled with cellular metabolism, which is severely compromised by glucose deprivation and elevated sodium chloride (NaCl) in the solid tumor microenvironment (TME). Here, we demonstrated that glucose restriction markedly impaired activation, cytotoxicity, and persistence of CAR-T cells while promoting exhaustion, whereas high NaCl partially reversed these defects. Overexpression of the sodium–glucose cotransporter SGLT2 in CAR-T cells to simultaneously enhance glucose and NaCl uptake led to stronger antitumor activity in multiple solid tumor xenograft models. Mechanistically, SGLT2 overexpression elevated glycolysis and mitochondrial fitness, inhibited ferroptosis, and activated the AKT-mTOR pathway. These findings establish a metabolic engineering strategy that boosts glucose utilization in CAR-T cells to overcome TME stress and enhance solid tumor control.