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This article aims to systematically analyze this \u2018double-edged sword\u2019 characteristic by providing an exhaustive review of the axis\u2019s functional spectrum across different diseases. Initially, we explore its bidirectional regulatory mechanisms within the tumor microenvironment, emphasizing the influence of tumor heterogeneity and the distinct roles of CXCL16 isoforms (membrane-bound and soluble) in determining functional outcomes. Subsequently, we broaden the discussion to encompass inflammatory diseases, examining the axis\u2019s potential as a predictive marker in these conditions and presenting the latest insights into its role in diseases such as asthma. Additionally, we provide a review of current advancements in drug development targeting this axis and elucidate its mechanisms of action. Ultimately, the paper underscores that accurately identifying the critical nodes where the CXCL16\/CXCR6 axis alters its function is the central challenge and opportunity for the development of targeted therapies.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1802735","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T04:21:21Z","timestamp":1784521281000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Advancements in understanding and treating CXCL16\/CXCR6 in tumors and in inflammatory diseases: a narrative review"],"prefix":"10.3389","volume":"17","author":[{"given":"Xiaohong","family":"Li","sequence":"first","affiliation":[{"name":"First Clinical Medical College, School of Pharmacy and School of Basic Medicine, Yunnan University of Chinese Medicine","place":["Kunming, China"]},{"name":"Department of Scientific Research, The Fifth Affiliated Hospital of Yunnan University of Chinese 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