Targeting PDPN+ CAFs enhances treatment efficacy of trastuzumab by reversing immunosuppressive microenvironment in HER2-positive breast cancer.

Trastuzumab, a humanized monoclonal antibody, is extensively used for HER2-positive (HER2+) breast cancer, yet acquired resistance remains a clinical challenge. Building on our prior discovery that PDPN-positive cancer-associated fibroblasts (PDPN+ CAFs) critically shape immunosuppressive microenvironments and mediate trastuzumab resistance, this study integrates bulk and single-cell transcriptomic data from patients with trastuzumab treatment to investigate the mechanisms associated with PDPN+ CAFs. We identified an augmented crosstalk between tumor endothelial cells (TECs) and CAFs, which represents a novel mechanism of trastuzumab resistance. It was found that CXCL12+ TECs activate and sustain PDPN+ CAFs' immunosuppressive phenotype via constitutive CXCL12 secretion. Furthermore, we pioneer the development of an anti-PDPN monoclonal antibody. In murine models, anti-PDPN antibody significantly enhances antitumor efficacy and prolongs progression-free survival of the mice. Our work reveals that TECs-CAFs crosstalk propagates trastuzumab resistance, and anti-PDPN delivers a mechanism-validated targeting strategy to reverse trastuzumab resistance.