TY  - JOUR
AU  - Zur, Raphaëlle Toledano
AU  - Zurinam, Shiran Didi
AU  - Radman, Maria
AU  - Funaro Balouka, Elia
AU  - Borodianskiy-Shteinberg, Tatiana
AU  - Saur, Dieter
AU  - Cohen, Cyrille J
TI  - Hexokinase2-engineered T cells display increased anti-tumor function.
JO  - Frontiers in immunology
VL  - 16
SN  - 1664-3224
CY  - Lausanne
PB  - Frontiers Media
M1  - DKFZ-2025-00705
SP  - 1477929
PY  - 2025
AB  - 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.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.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.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.
KW  - Hexokinase: genetics
KW  - Hexokinase: metabolism
KW  - Hexokinase: immunology
KW  - Humans
KW  - Animals
KW  - T-Lymphocytes: immunology
KW  - T-Lymphocytes: metabolism
KW  - T-Lymphocytes: transplantation
KW  - Mice
KW  - Tumor Microenvironment: immunology
KW  - Xenograft Model Antitumor Assays
KW  - Cell Line, Tumor
KW  - Glycolysis
KW  - Immunotherapy, Adoptive: methods
KW  - Neoplasms: immunology
KW  - Neoplasms: therapy
KW  - Neoplasms: metabolism
KW  - Cytokines: metabolism
KW  - Lymphocyte Activation
KW  - Female
KW  - T-cells (Other)
KW  - TCR (Other)
KW  - cellular immunotherapy (Other)
KW  - hexokinase 2 (Other)
KW  - immunometabolism (Other)
KW  - Hexokinase (NLM Chemicals)
KW  - HK2 protein, human (NLM Chemicals)
KW  - Cytokines (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40181966
C2  - pmc:PMC11965122
DO  - DOI:10.3389/fimmu.2025.1477929
UR  - https://inrepo02.dkfz.de/record/300244
ER  -