CD28 vs. 4-1BB Co-Stimulation in CAR T Cells: Metabolic Pathways in Nutrient-Depleted Tumor Microenvironments

This study compares CD28 vs. 4-1BB CAR T-cells, showing that CD28 drives glycolysis for rapid but short-lived effector responses, while 4-1BB promotes mitochondrial biogenesis and oxidative metabolism for sustained persistence. Data from functional assays demonstrated that CD28 CAR T-cells exhibit higher initial cytokine production but undergo accelerated exhaustion, whereas 4-1BB CARs maintain proliferative capacity and memory-like features over extended time points. Key correlations linked metabolism to outcomes – glycolysis strongly associated with exhaustion (r = +0.91), while oxidative capacity correlated with improved tumor control and survival (r = +0.92). Clinically, these results essentially highlight that the co-stimulatory domain influences not just the persistence but also long-term remission of the cell which helps tailor CAR designs to align with TME’s.