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

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.