{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T22:41:51Z","timestamp":1792190511921,"version":"4.4.0"},"reference-count":42,"publisher":"Wiley","issue":"35","license":[{"start":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:00:00Z","timestamp":1750723200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003787","name":"Natural Science Foundation of Hebei Province","doi-asserted-by":"publisher","award":["H2022206539"],"award-info":[{"award-number":["H2022206539"]}],"id":[{"id":"10.13039\/501100003787","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Tumor\u2010associated macrophages (TAMs) play a crucial role in tumor progression within the tumor microenvironment (TME) through phenotypic plasticity and functional modulation. While tunneling nanotubes (TNTs) mediate intercellular communication, their role in shaping TAMs phenotypes and function remains unclear. This study explores how TNTs facilitate the transfer of tumor\u2010derived materials, particularly fatty acids, to TAMs, affecting macrophage polarization and function. Single\u2010cell RNA sequencing identified heterogeneous macrophage subpopulations in the TME. Enrichment analysis pinpointed key substances transferred via TNTs. Lipidomics and metabolomics analyzed the fatty acids involved. In vitro and in vivo experiments validated TNTs\u2010mediated material transfer, and transcriptomic analysis revealed the associated signaling pathways. TNTs are the primary route for transferring tumor\u2010derived fatty acids, notably arachidonic acid (AA), to macrophages. This transfer reprogrammed TAMs from anti\u2010tumor CD5L\n                    <jats:sup>+<\/jats:sup>\n                    to pro\u2010tumor TREM2\n                    <jats:sup>+<\/jats:sup>\n                    phenotypes, increasing CCL18 secretion, reducing phagocytic activity, and impairing CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell proliferation. Mechanistically, AA activated the PI3K\u2010AKT pathway, driving TAMs polarization. These findings are confirmed in xenograft models, where TNTs\u2010induced TAMs exhibited enhanced pro\u2010tumor properties. TNTs\u2010mediated transfer of tumor\u2010derived AA reprograms TAMs via PI3K\u2010AKT activation, promoting immune suppression and tumor progression, highlighting TNTs and PI3K\u2010AKT as potential therapeutic targets in iCCA.\n                  <\/jats:p>","DOI":"10.1002\/advs.202500148","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T06:31:13Z","timestamp":1750746673000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Role of Tunneling Nanotubes in Arachidonic Acid Transfer and Macrophage Function Reprogramming in Intrahepatic Cholangiocarcinoma"],"prefix":"10.1002","volume":"12","author":[{"given":"Meiru","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Gastroenterology The Second Hospital of Hebei Medical University Hebei Key Laboratory of Gastroenterology Hebei Institute of Gastroenterology Hebei Clinical Research Center for Digestive Diseases  Shijiazhuang Hebei 050000 China"},{"name":"Department of Gastroenterology Hengshui People's Hospital  Hengshui Hebei 053000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shangyumeng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Preventive Medicine College of Public Health Hebei Medical University  Shijiazhuang 050017 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology The Second Hospital of Hebei Medical University Hebei Key Laboratory of Gastroenterology Hebei Institute of Gastroenterology Hebei Clinical Research Center for Digestive Diseases  Shijiazhuang Hebei 050000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology The Second Hospital of Hebei Medical University Hebei Key Laboratory of Gastroenterology Hebei Institute of Gastroenterology Hebei Clinical Research Center for Digestive Diseases  Shijiazhuang Hebei 050000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Hengshui People's Hospital  Hengshui Hebei 053000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Hengshui People's Hospital  Hengshui Hebei 053000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruolin","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology The Second Hospital of Hebei Medical University Hebei Key Laboratory of Gastroenterology Hebei Institute of Gastroenterology Hebei Clinical Research Center for Digestive Diseases  Shijiazhuang Hebei 050000 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