{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T16:24:32Z","timestamp":1774542272145,"version":"3.50.1"},"reference-count":66,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T00:00:00Z","timestamp":1756771200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32170660"],"award-info":[{"award-number":["32170660"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["20002150110"],"award-info":[{"award-number":["20002150110"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["22120230292"],"award-info":[{"award-number":["22120230292"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Adenocarcinoma of the esophagogastric junction (AEG) is increasingly recognized as a distinct gastrointestinal tumor type with a poor prognosis. However, the mechanisms driving AEG progression, particularly the interplay between metabolic reprogramming and the immune microenvironment, remain poorly understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We integrated multi-omics to profile the tumor microenvironment and metabolic reprogramming of AEG. Tumor tissues and paired normal adjacent tissues from AEG patients were subjected to single-cell RNA sequencing (<jats:italic>N<\/jats:italic>=11), spatial transcriptomics (<jats:italic>N<\/jats:italic>=4), and metabolomics analysis (<jats:italic>N<\/jats:italic>=26). Molecular experiments and animal models were used for validation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our analysis revealed an AEG-specific malignant subtype originating from the esophagogastric junction, characterized by heightened proliferation and poor differentiation. These malignant cells exhibited metabolic reprogramming marked by hyperactivation of the glutamine-arginine-spermine axis with concomitant spermine accumulation. Spermine was found to drive the polarization of tumor-associated macrophages into an APOE<jats:sup>+<\/jats:sup> immunosuppressive phenotype, thereby modulating the tumor immune microenvironment. Mechanistically, spermine promoted the phosphorylation of STAT3, thereby enhancing its binding affinity to the APOE promoter region and leading to enhanced transcriptional activation of APOE.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study identified AEG-like malignant cells as a high-risk subtype, revealed the metabolic-immune crosstalk driven by the spermine-STAT3-APOE axis in AEG progression, and provided potential targets for AEG metabolic intervention and immunotherapy.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2025.1636699","type":"journal-article","created":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T05:32:37Z","timestamp":1756791157000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Malignant epithelia cells-derived spermine induces APOE+ macrophages to suppress tumor immunity in adenocarcinoma of the esophagogastric junction"],"prefix":"10.3389","volume":"12","author":[{"given":"Yan","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhaoyang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huihui","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhenxiang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ye","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiqian","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinxing","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanping","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenfei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuchang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,2]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"2144","DOI":"10.1016\/j.ejca.2015.07.026","article-title":"Survival 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Hepatol"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"6091","DOI":"10.1038\/s41467-020-19949-6","article-title":"Genomic and transcriptomic alterations associated with drug vulnerabilities and prognosis in adenocarcinoma at the gastroesophageal junction","volume":"11","author":"Lin","year":"2020","journal-title":"Nat Commun"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1186\/s12885-020-6537-9","article-title":"Detection of early adenocarcinoma of the Esophagogastric junction by spraying an enzyme-Activatable fluorescent probe targeting dipeptidyl peptidase-iv","volume":"20","author":"Yamamoto","year":"2020","journal-title":"BMC Cancer"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1457","DOI":"10.1046\/j.1365-2168.1998.00940.x","article-title":"Classification of adenocarcinoma of the Oesophagogastric junction","volume":"85","author":"Siewert","year":"1998","journal-title":"Br J Surg"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1111\/dote.12540","article-title":"Recommendations for clinical staging (Ctnm) of cancer of the esophagus and Esophagogastric junction for the 8th edition Ajcc\/Uicc staging manuals","volume":"29","author":"Rice","year":"2016","journal-title":"Dis Esophagus"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1097\/SLA.0b013e31824beb95","article-title":"Should adenocarcinoma of the Esophagogastric junction be classified as esophageal cancer? 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metabolites profiling for characterization of lung and liver cancer using an Lc-tandem Ms method with multiple statistical data mining strategies: discovering potential cancer biomarkers in human plasma and urine","volume":"21","author":"Xu","year":"2016","journal-title":"Molecules"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"3601","DOI":"10.21873\/anticanres.12634","article-title":"Altered polyamine profiles in colorectal cancer","volume":"38","author":"Ven\u00e4l\u00e4inen","year":"2018","journal-title":"Anticancer Res"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"305","DOI":"10.3892\/ijo.2010.849","article-title":"Spermine accelerates hypoxia-initiated cancer cell migration","volume":"38","author":"Tsujinaka","year":"2011","journal-title":"Int J Oncol"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"1796","DOI":"10.1016\/j.immuni.2024.05.025","article-title":"Cellular Spermine targets Jak signaling to restrain cytokine-mediated 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