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

Jian Gu1, Yu Li2, Qiuyang Chen2

  • 1Jiangsu 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.

Cell
|December 25, 2025
PubMed

Insights

Regulatory T cells (Tregs) adapt to tumor environments by detoxifying ammonia, enhancing their immunosuppressive function and driving immunotherapy resistance. Targeting ammonia offers a potential strategy to boost anti-tumor immunity.

Area of Science:

  • Immunology
  • Metabolic pathways
  • Cancer biology

Background:

  • Mechanisms of regulatory T cell (Treg) adaptation in tumor metabolic microenvironments are unclear.
  • Tregs suppress anti-tumor immunity within harsh tumor conditions.

Purpose of the Study:

  • To elucidate how Tregs adapt to hepatocellular carcinoma's metabolic microenvironment.
  • To identify molecular mechanisms Tregs use for survival and immunosuppression.

Main Methods:

  • Spatial metabolomics and transcriptomics in human hepatocellular carcinoma.
  • X-ray crystallography to verify molecular interactions.
  • Analysis of Treg function in response to metabolic cues.

Main Results:

  • Hepatocellular carcinoma exhibits metabolic heterogeneity with high glutaminolysis and ammonia.
  • Tregs utilize the urea cycle (ASL) and spermine synthesis (SMS) to detoxify ammonia.
  • Spermine interacts with PPARγ, enhancing Treg oxidative phosphorylation and immunosuppression.
  • Ammonia from dying tumor cells reinforces Treg function, causing immunotherapy resistance.

Conclusions:

  • Tregs adapt to ammonia-rich tumor microenvironments via urea cycle and spermine synthesis.
  • Spermine-PPARγ interaction enhances Treg immunosuppressive function.
  • Ammonia production by tumor cells contributes to anti-PD-1 resistance.
  • Targeting ammonia metabolism in Tregs is a potential immunotherapy strategy.
Keywords:
Tregsammoniacancer immunotherapyglutaminolysismetabolic adaptationpolyamine metabolismurea cycle

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