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Tumor\u2010associated macrophages (TAMs) play a crucial role in promoting tumor metastasis and progression; however, the underlying mechanisms through which TAMs induce LN metastasis in GC remain poorly understood. This study demonstrates that low lipocalin\u20102 (LCN2) expression is associated with increased LN metastasis and shorter survival in GC. Functionally, LCN2 silencing significantly increases M2\u2010type TAM infiltration, lymphangiogenesis, and LN metastasis. Mechanistically, LCN2 downregulates the NF\u2010\u03baB pathway\u2010mediated CCL5 expression by interacting with Annexin A1, which inhibits K63\u2010 and M1\u2010linked ubiquitination of NEMO. Furthermore, LCN2\u2010regulated CCL5 recruits and repolarizes TAMs through the CCR5\/PI3K\/AKT\/GSK3\u03b2 axis, which subsequently promotes lymphangiogenesis and LN metastasis via vascular endothelial growth factor C (VEGFC) secretion. Additionally, interleukin\u201010 (IL\u201010) derived from M2\u2010type TAMs suppresses I\u03baB\u03b6 and its target gene,\n                    <jats:italic>LCN2<\/jats:italic>\n                    , in GC cells by promoting I\u03baB\u03b6 degradation, thereby establishing an IL\u201010\/I\u03baB\u03b6\/LCN2 positive\u2010feedback loop that sustains LCN2 suppression. These findings suggest that reduced LCN2 expression drives a positive feedback loop between tumor cells and TAMs that continuously enhances lymphangiogenesis and LN metastasis in GC. Therefore, targeting these related pathways may represent a promising therapeutic strategy for GC patients and LN metastasis.\n                  <\/jats:p>","DOI":"10.1002\/advs.202508352","type":"journal-article","created":{"date-parts":[[2025,8,30]],"date-time":"2025-08-30T09:52:57Z","timestamp":1756547577000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["An LCN2\u2010Dependent Positive\u2010Feedback Loop Between Gastric Cancer Cells and Tumor\u2010Associated\u2010Macrophages Mediates Lymphangiogenesis and Lymphatic Metastasis"],"prefix":"10.1002","volume":"12","author":[{"given":"Zhixin","family":"Huang","sequence":"first","affiliation":[{"name":"Division of Gastrointestinal Surgery Center the First Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou Guangdong 510080 China"},{"name":"Laboratory of Surgery the First Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou Guangdong 510080 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