{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T08:54:28Z","timestamp":1782118468186,"version":"3.54.5"},"reference-count":207,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>\n                    Metabolic reprogramming within the tumor microenvironment plays a pivotal role in tumor proliferation, progression, and immune evasion. Cancer cells exhibit altered lipid, glucose, and amino acid metabolism to adapt to hostile conditions such as hypoxia and nutrient deprivation. Particularly, ammonia metabolism has emerged as a critical aspect of tumor metabolic reprogramming. Oncogene mutations, such as those in\n                    <jats:italic>c-MYC<\/jats:italic>\n                    ,\n                    <jats:italic>KRAS<\/jats:italic>\n                    , and\n                    <jats:italic>p53<\/jats:italic>\n                    , regulate key enzymes involved in amino acid metabolism, which in turn affects tumor cell survival and proliferation. Elevated ammonia levels in the TME (Tumor Microenvironment) not only provide essential nitrogen for cell growth but also impair immune cell function, including T cells and natural killer cells, contributing to immune evasion. High ammonia concentrations suppress T cell activation and promote exhaustion, while interfering with natural killer cell cytotoxicity by hindering perforin maturation. Moreover, ammonia accumulation fosters an immunosuppressive microenvironment, influencing cytokine secretion and facilitating tumor metastasis. Targeting ammonia metabolism, in combination with immune checkpoint inhibitors, presents a promising therapeutic strategy to enhance immune responses and inhibit tumor progression. This review consolidates recent findings on the role of ammonia metabolism in the TME, highlighting its potential as a therapeutic target to improve cancer treatment outcomes.\n                  <\/jats:p>","DOI":"10.3389\/fcell.2026.1826809","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T08:43:01Z","timestamp":1782117781000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Ammonia metabolic reprogramming in the tumor microenvironment: emergence of an immunosuppressive niche"],"prefix":"10.3389","volume":"14","author":[{"given":"Zihao","family":"Ye","sequence":"first","affiliation":[{"name":"Department of Urology II, The First Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Urology II, The First Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanhao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology II, The First Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruizhe","family":"Ye","sequence":"additional","affiliation":[{"name":"School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingliang","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Urology, China-Japan Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Urology II, The First Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baoshan","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Urology II, The First Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,22]]},"reference":[{"key":"B1","volume-title":"A Multicenter Phase 2 Study of the Glutaminase Inhibitor CB-839 in Combination with Paclitaxel in Patients with Advanced Triple Negative Breast Cancer (TNBC) Including Patients of African Ancestry and Non-African Ancestry","year":"2017"},{"key":"B2","volume-title":"A Phase 1\/2 Study of INCB001158 in Combination with Chemotherapy in Subjects with Solid Tumors","year":"2017"},{"key":"B3","volume-title":"A Phase 1b\/2 Study of Glutamine Antagonist DRP-104 in Combination with Durvalumab in Patients with Advanced Stage Fibrolamellar Hepatocellular Carcinoma (FLC)","year":"2023"},{"key":"B4","volume-title":"A Phase 2 Randomized, Multicenter, Double-Blind Study of the Glutaminase Inhibitor Telaglenastat with Pembrolizumab and Chemotherapy Versus Placebo with Pembrolizumab and Chemotherapy in First-Line, Metastatic KEAP1\/NRF2-Mutated, Nonsquamous, Non-Small Cell Lung Cancer (NSCLC)","year":"2020"},{"key":"B5","volume-title":"A Phase 2 Study of DRP-104, a Glutamine Antagonist, in Patients with NFE2L2\/KEAP1-altered Non-small Cell Lung Cancer","year":"2025"},{"key":"B6","volume-title":"A Phase I\/II Study Evaluating the Safety and Activity of Pegylated Recombinant Human Arginase (BCT-100) in Relapsed\/Refractory Cancers of Children and Young Adults","year":"2018"},{"key":"B7","volume-title":"A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study Comparing CB-839 in Combination with Everolimus (CBE) vs. Placebo with Everolimus (PboE) in Patients with Advanced or Metastatic Renal Cell Carcinoma (RCC)","year":"2017"},{"key":"B8","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.lungcan.2013.08.008","article-title":"Interaction between non-small-cell lung cancer cells and fibroblasts via enhancement of TGF-\u03b2 signaling by IL-6","volume":"82","author":"Abulaiti","year":"2013","journal-title":"Lung Cancer"},{"key":"B9","doi-asserted-by":"publisher","first-page":"10647","DOI":"10.1073\/pnas.1534833100","article-title":"Cholesterol-induced conformational change in SCAP enhanced by Insig proteins and mimicked by cationic amphiphiles","volume":"100","author":"Adams","year":"2003","journal-title":"Proc. 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