An LCN2‐Dependent Positive‐Feedback Loop Between Gastric Cancer Cells and Tumor‐Associated‐Macrophages Mediates Lymphangiogenesis and Lymphatic Metastasis

Abstract Lymph node (LN) metastasis is a major determinant of poor prognosis in patients with gastric cancer (GC). Tumor‐associated 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‐2 (LCN2) expression is associated with increased LN metastasis and shorter survival in GC. Functionally, LCN2 silencing significantly increases M2‐type TAM infiltration, lymphangiogenesis, and LN metastasis. Mechanistically, LCN2 downregulates the NF‐κB pathway‐mediated CCL5 expression by interacting with Annexin A1, which inhibits K63‐ and M1‐linked ubiquitination of NEMO. Furthermore, LCN2‐regulated CCL5 recruits and repolarizes TAMs through the CCR5/PI3K/AKT/GSK3β axis, which subsequently promotes lymphangiogenesis and LN metastasis via vascular endothelial growth factor C (VEGFC) secretion. Additionally, interleukin‐10 (IL‐10) derived from M2‐type TAMs suppresses IκBζ and its target gene, LCN2 , in GC cells by promoting IκBζ degradation, thereby establishing an IL‐10/IκBζ/LCN2 positive‐feedback 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.