ArticleCancer research2025
Ammonia Suppresses the Antitumor Activity of Natural Killer Cells and T Cells by Decreasing Mature Perforin.
Article in Cancer research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Cell therapy manufacturing at full clinical scale: enhancing the quality CAR-T cell therapy starting materials through massively parallel automated microfluidic cell sorting.Lab on a chip · 2026Article
- Overview of glutamine metabolism in stromal components of the tumor microenvironment and potential anti-tumor therapies.Genes & diseases · 2026Review
- Reprogramming of nitrogen metabolism in tumors: mechanisms and therapeutic implications.Amino acids · 2026Review
- Decorin facilitates T cell-mediated antitumor immunity and augments the efficacy of anti-PD1 immunotherapy.Cancer immunology, immunotherapy : CII · 2026Article
- Extracellular granzyme K enhances PD-L1 transcription and stability via F2RL1 activation to facilitate tumor immune evasion in lung adenocarcinoma.Journal for immunotherapy of cancer · 2026Article
- Ammonia metabolic reprogramming in the tumor microenvironment: emergence of an immunosuppressive niche.Frontiers in cell and developmental biology · 2026Review
- Integrating T cell signaling and metabolism to enhance T cell engager responses in solid tumors.Frontiers in immunology · 2026Review
- Ammonia signaling network: the intersection of tumor metabolism, epigenetics, and metastasis.Frontiers in endocrinology · 2026Review
- Ammonia in cancer: dual roles and therapeutic strategies.Cancer cell international · 2025Review
- Ammonia metabolism and ammonia-induced cell death: role in cancer therapy.Cell communication and signaling : CCS · 2025Review
- Novel roles of ammonia in physiology and cancer.Journal of molecular cell biology · 2025Review
- Ammonium metabolism rewiring in the prostate cancer microenvironment: Mechanisms and clinical prospects.Frontiers in oncology · 2025Review
- MEGF8-driven metabolic reprogramming and immune evasion define a high-risk subtype of endometriosis-associated ovarian cancer.American journal of translational research · 2025Article
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Authors and funding
28 authors.
Funding
Abstract
Immunotherapy revolutionized cancer treatment in the last decade. Both NK cells and T cells are key components of host immunity against malignant cells that are being extensively investigated in the field of cancer immunotherapy. While approaches have been developed to improve the antitumor activity of NK and T cells, the tumor microenvironment remains an obstacle to effective NK and T-cell-based therapies. Here, we demonstrated that cancer-conditioned medium suppresses the antitumor activity of NK cells. Ammonia, a by-product of cancer cell metabolism, accumulated in cancer-conditioned medium and in the tumor microenvironment, and impaired the cytotoxicity of NK cells as well as the efficacy of antibody-based and chimeric antigen receptor (CAR) NK and CAR T-cell-based therapies in vitro. Ammonia induced NK and T-cell dysfunction by decreasing the amount of mature perforin in secretory lysosomes, which was dependent on its lysosomotropic features and ability to increase pH in acidic compartments. These findings demonstrate that, in addition to its previously described role in promoting tumor growth as a source of nitrogen for tumor biomass, ammonia promotes tumor immune escape by inhibiting both NK and CAR T-cell cytotoxicity. SIGNIFICANCE: Ammonia is elevated in the tumor microenvironment and functions as an immunoinhibitory metabolite in cancer by reducing perforin levels, inhibiting NK and T-cell-mediated immunity and limiting the efficacy of immunotherapies.
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Registered trials
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