On-demand GLUT3 expression augments CAR T cell metabolic fitness and antitumor efficacy in preclinical models of glioblastoma

The clinical success of chimeric antigen receptor T cell (CAR T cell) therapy in hematologic malignancies has prompted its application for refractory solid tumors, including glioblastoma (GBM). However, CAR T cell trials against solid tumors have failed to show clinical efficacy thus far. Here, we show that the dysfunction of CAR T cells in GBM is attributed, at least, in part, to glucose deficiency in the tumor microenvironment (TME) driven by the substantial consumption of glucose by cancer cells. Engineering CAR T cells to continuously express glucose transporter 3 (GLUT3), a high-affinity glucose transporter, restored their cytokine production and killing activity. However, although CAR T cells with stable GLUT3 expression induced tumor reduction in a preclinical GBM model, their overactivation led to adverse events and mouse death. In contrast, on-demand GLUT3-expressing CAR T cells, in which GLUT3 transcription was driven by the nuclear translocation of nuclear factor of activated T cells (NFAT) as a consequence of target antigen stimulation, exhibited enhanced metabolic fitness and increased antitumor efficacy, leading to long-lasting tumor control in intracranial human GBM cell xenograft models while preventing adverse events. We propose that on-demand enhancement of metabolic fitness, such as at the time of exposure to tumor antigens, is a concept for boosting the antitumor efficacy of CAR T cells against solid tumors.

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Publication Details

Journal
Science Translational Medicine
Published
2026-04-15
DOI
https://doi.org/10.1126/scitranslmed.adu3532
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
0.00

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article

On-demand GLUT3 expression augments CAR T cell metabolic fitness and antitumor efficacy in preclinical models of glioblastoma

Fumiharu Ohka, Hiroyuki Mizoguchi, Atsushi Enomoto, Yuichiro Tsukada et al.
Science Translational Medicine
CAR-T cell therapy research
article

On-demand GLUT3 expression augments CAR T cell metabolic fitness and antitumor efficacy in preclinical models of glioblastoma

Fumiharu Ohka, Hiroyuki Mizoguchi, Atsushi Enomoto, Yuichiro Tsukada, Hiroyoshi Nishikawa, Junya Yamaguchi, Shohei Koyama, Yi-Tzu Lin, Daisuke Sugiyama, Ryuzo Ueda, Kazuya Motomura, Keisuke Watanabe, Masaaki Ito, Akihito Nagata, Atsushi Natsume, Kota Itahashi, Hitomi Nishinakamura, Yukihiro Shiraki, Shinichiro Kato, Ryuta Saito, Sachi Maeda, Akihiro Nakamura, Yuka Maeda
article en

Abstract

The clinical success of chimeric antigen receptor T cell (CAR T cell) therapy in hematologic malignancies has prompted its application for refractory solid tumors, including glioblastoma (GBM). However, CAR T cell trials against solid tumors have failed to show clinical efficacy thus far. Here, we show that the dysfunction of CAR T cells in GBM is attributed, at least, in part, to glucose deficiency in the tumor microenvironment (TME) driven by the substantial consumption of glucose by cancer cells. Engineering CAR T cells to continuously express glucose transporter 3 (GLUT3), a high-affinity glucose transporter, restored their cytokine production and killing activity. However, although CAR T cells with stable GLUT3 expression induced tumor reduction in a preclinical GBM model, their overactivation led to adverse events and mouse death. In contrast, on-demand GLUT3-expressing CAR T cells, in which GLUT3 transcription was driven by the nuclear translocation of nuclear factor of activated T cells (NFAT) as a consequence of target antigen stimulation, exhibited enhanced metabolic fitness and increased antitumor efficacy, leading to long-lasting tumor control in intracranial human GBM cell xenograft models while preventing adverse events. We propose that on-demand enhancement of metabolic fitness, such as at the time of exposure to tumor antigens, is a concept for boosting the antitumor efficacy of CAR T cells against solid tumors.

Science Translational MedicineVol. 18(845)
Shizuoka Cancer Center (JP), Nagoya University Hospital (JP), Immunité et Cancer (FR), Chiba Cancer Center (JP), National Cancer Center Hospital East (JP), National Cancer Research Institute (GB), Nagoya University (JP), Kindai University (JP)
Kobayashi Foundation for Cancer Research
Good health and well-being
Openalex Percentile: Top 22%
CAR-T cell therapy research
DOISourceOpenAlex
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