2025/12/24 by Jian Gu, Li Yu, Q. Chen +13 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Cancer, Hypoxia, and Metabolism #Cancer Research and Treatments #Cancer Immunotherapy and Biomarkers
paper · doi:10.1016/j.cell.2025.11.034
openalex publication_date 2025/12/24 · openalex created_date 2025/12/24 · openalex updated_date 2026/07/23
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.