Hypoxia-driven TCF21/CCL11 axis in GCMSCs orchestrates macrophage polarization and lymphatic remodeling to promote gastric cancer lymph node metastasis

Lymph node metastasis (LNM) is a primary critical factor for gastric Cancer (GC) prognosis, fundamentally driven by the adaptive remodeling of the tumor microenvironment (TME). While gastric cancer-associated mesenchymal stem cells (GCMSCs) are recognized as pivotal orchestrators of the tumor niche, the paracrine mediators governing LNM remain poorly defined. In this study, integrative transcriptomic and cytokine profiling identified CCL11 as the most significantly upregulated chemokine in GCMSCs. Clinical analysis demonstrated that elevated CCL11 expression in tumor tissues correlated with advanced LNM and dismal overall survival. Furthermore, a signature score derived from CCL11⁺ MSC subclusters, identified via single-cell RNA Sequencing, was positively associated with advanced clinical stages and poor prognosis. Serum CCL11 levels further exhibited high diagnostic efficacy for gastric Cancer (AUC:0.8131) and moderate predictive value for lymph node metastasis (AUC:0.7848). Intriguingly, despite these robust clinical associations, exogenous CCL11 failed to directly influence the proliferative or migratory capacity of GC cell lines. This discrepancy was resolved by our finding that the cognate receptor CCR3 was virtually absent on the malignant epithelium but selectively enriched on macrophages and lymphatic endothelial cells (LECs). Functionally, GCMSC-derived CCL11 drove M2 macrophage polarization to bolster tumor stemness and chemoresistance, while simultaneously remodeling LECs to facilitate lymphangiogenesis and transendothelial migration. Mechanistically, hypoxic stress triggered the nuclear translocation of TCF21, which directly transactivated the CCL11 promoter in GCMSCs. Together, these findings identify the hypoxia-TCF21-CCL11 axis as a key driver of the GC metastatic niche, highlighting the indispensable significance of stromal-derived molecules in deciphering metastatic complexity and identifying promising targets for early diagnosis and strategic therapeutic intervention.