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However, its function in cholangiocarcinoma (CCA) is underexplored. Tumor profiling for\n                    <jats:italic>CXCL6<\/jats:italic>\n                    is performed using a public database. Both in vitro and in vivo experiments are utilized to evaluate the oncogenic effects of CXCL6 on CCA. Additionally, RNA\u2010Seq is employed to detect transcriptomic changes related to CXCL6 expression in CCA cells and neutrophils. Molecular docking, fluorescence colocalization, and Co\u2010IP are used to elucidate a direct interaction between JAKs and CXCR1\/2. Additionally, LC\u2010MS lipidomics and explored the impact of CXCL6 on immunotherapy in vivo. CXCL6 is upregulated in CCA tissues and promoted the proliferation and metastasis of CCA. Mechanistically, CXCL6 regulated the CXCR1\/2\u2010JAK\u2010STAT\/PI3K axis in CCA via autocrine signaling, leading to lipid metabolic reprogramming, and promoted neutrophil extracellular traps (NETs) formation by activating the RAS\/MAPK pathway in neutrophils. Eventually, NETs formation induced immunotherapy resistance in CCA by blocking CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell infiltration. CXCL6 modulates CCA progression through the CXCR1\/2\u2010JAK\u2010STAT\/PI3K axis and reshaping its lipid metabolism. CXCL6 also mediates immunotherapy resistance through NETs, which may be a potential therapeutic target and biomarker for CCA.\n                  <\/jats:p>","DOI":"10.1002\/advs.202503009","type":"journal-article","created":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T19:57:56Z","timestamp":1746043076000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["CXCL6 Reshapes Lipid Metabolism and Induces Neutrophil Extracellular Trap Formation in Cholangiocarcinoma Progression and Immunotherapy Resistance"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3710-6484","authenticated-orcid":false,"given":"Tian","family":"He","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary Surgery and Liver Transplantation Liver Cancer Institute and Zhongshan Hospital Fudan University Shanghai 200032 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