VEGFC as a prognostic cytokine biomarker linking lymph node metastasis to immune suppression in breast cancer

Backgrounds: Lymph node metastasis is a critical determinant of breast cancer prognosis, yet the specific microenvironmental cytokines driving this process remain elusive. This study aims to identify key prognostic cytokines linking nodal metastasis to tumor microenvironment (TME) remodeling and to evaluate their clinical utility. Methods: A predefined panel of 176 microenvironmental genes was evaluated using differential expression analysis and the Least Absolute Shrinkage and Selection Operator (LASSO) algorithm on the TCGA-BRCA cohort to identify optimal predictors of nodal metastasis. Prognostic value was assessed via Kaplan-Meier, subgroup, and multivariate Cox regression analyses, and validated across five independent GEO datasets. Immune infiltration and therapeutic potential were evaluated using Gene Set Enrichment Analysis (GSEA), CIBERSORT deconvolution, pharmacogenomic screening, and molecular docking simulations. Results: Vascular Endothelial Growth Factor C (VEGFC) emerged as the top biomarker significantly upregulated in node-positive tumors. Multivariate analysis confirmed that VEGFC acts as a robust, independent predictor of poor relapse-free survival (RFS). Notably, subgroup analyses revealed this prognostic penalty is exceptionally pronounced in hormone receptor-positive Luminal A and B subtypes. Mechanistically, elevated VEGFC is strongly associated with an immunosuppressive “cold” TME, characterized by reduced cytotoxic CD8+ T-cell infiltration and enriched M2-macrophage polarization across multiple algorithms. Furthermore, pharmacogenomic analyses and docking simulations indicated potential sensitivity to PI3K/AKT inhibitors in VEGFC-high tumors. Conclusions: VEGFC is a robust, independent precision biomarker specifically indicating poor prognosis in Luminal breast cancers. It is significantly associated with an immune-excluded TME, suggesting that targeting the VEGFC axis may offer a novel strategy to reverse immune evasion.