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Peer-reviewedCC BY 4.0Advanced Science

18F‐FGln PET/CT Imaging of Glutamine Uptake Has Potential for Predicting Immunotherapy Response in Hepatocellular Carcinoma

  • Yi Liu1,2,3,4,5
  • Jindian Li1,3,4,5
  • Xiaoyu Pan1,3,4,5
  • Xiaoping Xu1,3,4,5
  • Xuan Huang1,3,4,5
  • Simin He1,3,4,5
  • Jianping Zhang1,3,4,5
  • Fei Liu1,3,4,5
  • Shaoli Song1,3,4,5
5 affiliations
  1. 1Department of Nuclear Medicine Fudan University Shanghai Cancer Center Shanghai China
  2. 2Department of Nuclear Medicine Clinical Oncology School of Fujian Medical University Fujian Cancer Hospital Fuzhou China
  3. 3Department of Oncology Shanghai Medical College Fudan University Shanghai China
  4. 4Center For Biomedical Imaging Fudan University Shanghai China
  5. 5Shanghai Engineering Research Center of Molecular Imaging Probes Shanghai China
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Abstract

We investigated whether glutamine (Gln) uptake, imaged by 18F‐(2S,4R)‐4‐fluoroglutamine (18F‐FGln) PET/CT, could predict and modulate immunotherapy response in hepatocellular carcinoma (HCC). Analysis of the Cancer Genome Atlas (TCGA)‐Liver Hepatocellular Carcinoma (LIHC) dataset revealed that SLC1A5 expression—which encodes a primary Gln uptake channel in HCC cells—was significantly associated with poor prognosis, higher tumor grade, and an immunosuppressive tumor microenvironment. In murine HCC models, tumors with high 18F‐FGln uptake exhibited elevated Slc1a5 expression and poor response to anti‐PD‐1 therapy, whereas low‐uptake tumors were more sensitive to immunotherapy. Genetic knockdown of Slc1a5 reduced 18F‐FGln uptake, enhanced anti‐PD‐1 efficacy, increased cytotoxic T lymphocyte infiltration, and decreased regulatory T cell abundance. Transcriptomic and single‐cell analyses revealed activation of antitumor immune pathways and reprogramming toward an immune‐inflamed phenotype after Slc1a5 suppression. V‐9302 decreased tumor Gln uptake, as measured by 18F‐FGln PET/CT, and sensitized HCC to PD‐1 blockade. In patient‐derived organoid‐T cell co‐culture systems, low‐SLC1A5 organoids were susceptible to PD‐1 blockade, whereas high‐SLC1A5 organoids were resistant, consistent with 18F‐FGln PET/CT findings. These results identify Gln uptake as a checkpoint of immune evasion in HCC and support that 18F‐FGln PET/CT has the potential to predict and monitor immunotherapy response.

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Cite

BibTeXRIS
BibTeX
@article{liu202618ffgln,
  title = {{18F‐FGln PET/CT Imaging of Glutamine Uptake Has Potential for Predicting Immunotherapy Response in Hepatocellular Carcinoma}},
  author = {Yi Liu and Jindian Li and Xiaoyu Pan and Xiaoping Xu and Xuan Huang and Simin He and Jianping Zhang and Fei Liu and Shaoli Song},
  journal = {Advanced Science},
  year = {2026},
  month = nov,
  doi = {10.1002/advs.78622},
  url = {https://doi.org/10.1002/advs.78622},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - 18F‐FGln PET/CT Imaging of Glutamine Uptake Has Potential for Predicting Immunotherapy Response in Hepatocellular Carcinoma
AU  - Yi Liu
AU  - Jindian Li
AU  - Xiaoyu Pan
AU  - Xiaoping Xu
AU  - Xuan Huang
AU  - Simin He
AU  - Jianping Zhang
AU  - Fei Liu
AU  - Shaoli Song
PY  - 2026
DA  - 2026/11/03
JO  - Advanced Science
DO  - 10.1002/advs.78622
UR  - https://doi.org/10.1002/advs.78622
AB  - We investigated whether glutamine (Gln) uptake, imaged by 18F‐(2S,4R)‐4‐fluoroglutamine (18F‐FGln) PET/CT, could predict and modulate immunotherapy response in hepatocellular carcinoma (HCC). Analysis of the Cancer Genome Atlas (TCGA)‐Liver Hepatocellular Carcinoma (LIHC) dataset revealed that SLC1A5 expression—which encodes a primary Gln uptake channel in HCC cells—was significantly associated with poor prognosis, higher tumor grade, and an immunosuppressive tumor microenvironment. In murine HCC models, tumors with high 18F‐FGln uptake exhibited elevated Slc1a5 expression and poor response to anti‐PD‐1 therapy, whereas low‐uptake tumors were more sensitive to immunotherapy. Genetic knockdown of Slc1a5 reduced 18F‐FGln uptake, enhanced anti‐PD‐1 efficacy, increased cytotoxic T lymphocyte infiltration, and decreased regulatory T cell abundance. Transcriptomic and single‐cell analyses revealed activation of antitumor immune pathways and reprogramming toward an immune‐inflamed phenotype after Slc1a5 suppression. V‐9302 decreased tumor Gln uptake, as measured by 18F‐FGln PET/CT, and sensitized HCC to PD‐1 blockade. In patient‐derived organoid‐T cell co‐culture systems, low‐SLC1A5 organoids were susceptible to PD‐1 blockade, whereas high‐SLC1A5 organoids were resistant, consistent with 18F‐FGln PET/CT findings. These results identify Gln uptake as a checkpoint of immune evasion in HCC and support that 18F‐FGln PET/CT has the potential to predict and monitor immunotherapy response.
SN  - 2198-3844
ER  -