The Glucose Transporter 5 Enhances CAR-T Cell Metabolic Function and Anti-tumour Durability

Area of Science:

• Immunology
• Metabolic Engineering
• Oncology

Background:

• Activated T cells rely on aerobic glycolysis for energy.
• Glucose transporters (GLUTs) are crucial for T cell metabolism and anti-tumour activity.
• Fructose metabolism in T cells, particularly via GLUT5, remains underexplored for CAR-T cell enhancement.

Approach:

• Investigated the role of GLUT5 in CAR-T cell metabolism using fructose as an alternative fuel source.
• Utilized tracer technology (¹³C₆ fructose) to track metabolic reprogramming in CAR-T cells.
• Assessed CAR-T cell function, including cytotoxicity and migration, in glucose-depleted conditions.

Key Points:

• GLUT5 expression enables T cells to utilize fructose, supporting glycolytic capacity and ATP production in glucose-free conditions.
• Fructose fuels CAR-T cell expansion, cytotoxicity, and migration, enhancing their effector functions.
• GLUT5 expression improved anti-tumour activity in an acute myeloid leukaemia (AML) xenograft model, even without fructose supplementation.

Conclusions:

• GLUT5 enhances CAR-T cell resilience and anti-tumour function in fructose-rich tumour microenvironments.
• GLUT5 offers a novel strategy to overcome glucose depletion and improve CAR-T cell efficacy.
• This metabolic engineering approach has direct translational relevance for improving cancer immunotherapy.