TGF-α/EGFR-mediated lymphatic metastasis reveals a repositionable therapeutic target in breast cancer

Abstract 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. Lymphatic endothelial cells (LECs) were identified as a tumor-associated source of TGF-α, both in a murine model and in human breast cancer, particularly upon stimulation with TGF-β1, a cytokine commonly overexpressed in breast tumors associated with lymph metastasis. We found that TGF-α–EGFR interactions elicit directional migration via STAT3 signaling, whereas the co-secreted ligand CTGF, enriched in blood endothelial cells, suppressed 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 resulted in increased cellularity in tumor-draining lymph nodes and reduced CD8⁺ T-cell representation. Together, these findings reveal a role for the TGF-α/EGFR axis in lymph metastasis and propose a rationale for repositioning EGFR-targeted therapies toward targeting early metastatic spread and immunomodulation in breast cancer.