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Hexokinase2-engineered T cells display increased anti-tumor function
Raphaëlle Toledano Zur1, Shiran Didi Zurinam1, Maria Radman1
1The Laboratory of Tumor Immunology and Immunotherapy, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
Background:
T cells face significant metabolic challenges in the tumor microenvironment (TME), where cancer cells monopolize critical nutrients like glucose and amino acids. This metabolic competition supports tumor growth while impairing T-cell anti-tumor responses, partly by reducing glycolytic function. Hexokinase 2 (HK2), a key enzyme in glycolysis, plays a pivotal role in maintaining T-cell functionality.
Methods:
To enhance T-cell function, primary human T cells were genetically engineered to overexpress HK2 alongside a tumor-specific receptor. These engineered T cells were tested in vitro and in vivo to evaluate their metabolic and therapeutic efficacy.
Results:
HK2-engineered T cells exhibited increased glycolytic capacity, leading to enhanced cytokine secretion, activation marker expression, and metabolic activity compared to controls. In vivo studies using a human tumor xenograft model demonstrated the superior therapeutic efficacy of HK2-engineered T cells, including delayed tumor growth and improved survival.
Conclusion:
HK2 overexpression improves T-cell metabolic fitness and functionality in hostile TMEs, offering a promising foundation for the development of next-generation immunotherapies targeting T-cell metabolism.
