TGF-α/EGFR chemotaxis drives lymphatic metastasis and early immune suppression, revealing a repositionable therapeutic target in breast cancer

The epidermal growth factor receptor (EGFR) is a well-established oncogenic driver in multiple epithelial cancers, yet its role in breast cancer remains elusive, with EGFR-targeted therapies showing limited clinical efficacy. Here, we demonstrate that EGFR promotes selective lymphatic dissemination in triple-negative breast cancer through a chemotactic mechanism involving the EGFR ligand TGF-α. Using murine and human breast cancer models, we identify lymphatic endothelial cells (LECs) as a tumor-associated source of TGF-α, particularly upon stimulation with TGF-β1, a cytokine commonly overexpressed in breast tumors. We show that TGF-α–EGFR interactions elicit directional migration via STAT3 signaling, whereas the co-secreted ligand CTGF, enriched in blood endothelium, suppresses migration. Pharmacologic blockade of TGF-α with Fepixnebart, a first-in-class ligand-neutralizing antibody targeting TGF-α and previously not tested in oncologic indications, significantly inhibited early lymph metastasis of EGFR⁺ tumor cells. Furthermore, EGFR overexpression accelerated immune suppression in tumor-draining lymph nodes, suggesting a link between early dissemination and pre-metastatic niche formation. Together, these findings reveal an unexpected, growth-independent function for EGFR in lymph metastasis and propose a rationale for repositioning EGFR-targeted therapies toward targeting early metastatic spread and immunosuppression in breast cancer.