2. Academic Validation
  3. Tumor-produced ammonia is metabolized by regulatory T cells to further impede anti-tumor immunity

Tumor-produced ammonia is metabolized by regulatory T cells to further impede anti-tumor immunity

  • Cell. 2025 Dec 24:S0092-8674(25)01369-8. doi: 10.1016/j.cell.2025.11.034.
Jian Gu 1,  Yu Li 2,  Qiuyang Chen 2,  Ziyan Song 2,  Qufei Qian 2,  Yuan Liang 3,  Tianning Huang 2,  Lei Qiao 2,  Xiangyu Li 2,  Miao Yu 2,  Mu Liu 2,  Jinren Zhou 2,  Qing Shao 2,  Xiaozhang Xu 2,  Robert Zeiser 4,  Ling Lu 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Organ Transplantation and Transplant Immunology and Hepatobiliary Center, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Collaborative Innovation Center for Cancer Personalized Medicine and Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. Electronic address: [email protected].
  • 2 Collaborative Innovation Center for Cancer Personalized Medicine and Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 3 School of Biological Science & Medical Engineering, Southeast University, Nanjing, China.
  • 4 Faculty of Medicine, Clinic for Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University Medical Center Freiburg, Freiburg, Germany.
  • 5 Jiangsu Key Laboratory of Organ Transplantation and Transplant Immunology and Hepatobiliary Center, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Collaborative Innovation Center for Cancer Personalized Medicine and Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. Electronic address: [email protected].
PMID: 41448182 DOI: 10.1016/j.cell.2025.11.034
Abstract

Mechanisms of adaptation of regulatory T cells (Tregs) to harsh tumor metabolic microenvironments for suppression of anti-tumor immunity remain largely unclear. Here, using spatial metabolomics and transcriptomics, we show that human hepatocellular carcinoma harbored metabolically heterogeneous subregions characterized by high glutaminolysis and ammonia contents, where Tregs were frequently present but CD8+ and CD4+ effector T cells die. We found Tregs used the urea cycle to detoxify ammonia by upregulating argininosuccinate lyase (ASL); meanwhile, ammonia was also converted to spermine by the FOXP3 transcription factor regulated spermine synthase (SMS). A direct interaction between spermine and PPARγ was verified by X-ray crystallography, leading to comprehensively modulating the transcription of multiple mitochondrial complex proteins to enhance Oxidative Phosphorylation and immunosuppression of Tregs. Clinically, anti-PD-1-treated dying tumor cells used transdeamination to release ammonia, which reinforced Treg function, leading to immunotherapeutic resistance. Targeting ammonia production to suppress Tregs presents a potential strategy for anti-tumor immunotherapy.

Keywords

Tregs; ammonia; cancer immunotherapy; glutaminolysis; metabolic adaptation; polyamine metabolism; urea cycle.

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