{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T15:58:14Z","timestamp":1792425494990,"version":"4.5.0"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T00:00:00Z","timestamp":1759363200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100015375","name":"Affiliated Hospital of Southwest Medical University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100015375","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>This study aims to investigate the relationship between tumor cell glutamine metabolism and CD8 T cells, with the goal of providing new insights to improve immunotherapy for pancreatic cancer.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using the The Cancer Genome Atlas \u2013 Pancreatic Adenocarcinoma (TCGA-PAAD) cohort, we computed gene expression scores related to glutamine metabolism and stratified patients into high- and low-score groups. Prognosis and differences in immune cell anti-tumor activity were compared between these groups. We further utilized single-cell RNA sequencing data to quantitatively assess the expression of glutamine metabolism-related pathways in tumor cells. Based on tumor-specific glutamine metabolism gene expression, patients were again classified into high- and low-score groups. The immune remodeling effects exerted by tumor cell glutamine metabolism on CD8 T cells were subsequently investigated. To examine the impact of perturbing glutamine metabolism within the tumor microenvironment on CD8 T cell phenotype and the efficacy of PD-1 inhibitors, we conducted <jats:italic>in vivo<\/jats:italic> animal experiments.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>we analyzed the pancreatic cancer dataset in the cancer gene atlas database. We found that tumor glutamine metabolism was negatively correlated with patient prognosis and anti-tumor activity. Next, we defined two types of CD8 effector T cells in single-cell RNA sequencing data, namely, effector memory T cells (CD8-Tem) and terminally differentiated effector memory T cells (CD8-Temra). Under the pressure of high glutamine metabolism in tumor cells, the cytotoxicity of the CD8-Tem subset was reduced, and its immaturity score increased, while the exhaustion score of the CD8-Temra subset increased. Pseudotime analysis showed that CD8-Tn in the low-scoring group mainly developed into CD8-Tem subset, and its immune activation pathway was significantly upregulated. In addition, we found that the glutamine metabolism inhibitor JHU083 promoted the infiltration of CD4 and CD8 T cells and T\u00a0lymphocyte differentiation, and increased the efficacy of PD-1 inhibitors. Glutamine inhibitors can inhibit the apoptosis of immune cells in the tumor microenvironment, while promoting CD8 T cells activation and cytotoxicity increase.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Inhibition of glutamine metabolism within the pancreatic cancer microenvironment results in reduced apoptosis of immune cells, heightened activation and cytotoxicity of CD8 T cells, and a substantial enhancement in the therapeutic efficacy of immunotherapy.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1599252","type":"journal-article","created":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T12:05:07Z","timestamp":1759406707000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Suppressing glutamine metabolism in the pancreatic cancer microenvironment can enhance the anti-tumor effect of CD8 T cells and promote the efficacy of immunotherapy"],"prefix":"10.3389","volume":"16","author":[{"given":"Jun","family":"Fan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yisheng","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunde","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maoshan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21654","article-title":"Cancer statistics, 2021","volume":"71","author":"Siegel","year":"2021","journal-title":"CA: Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-0155","article-title":"Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States","volume":"74","author":"Rahib","year":"2014","journal-title":"Cancer Res"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/cancers10010024","article-title":"Contemporary management of localized resectable pancreatic cancer","volume":"10","author":"Kommalapati","year":"2018","journal-title":"Cancers"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30974-0","article-title":". 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