CD155/PVR as a determinant of anti-HER2 therapy sensitivity in breast cancer

CD155 (poliovirus receptor, PVR) is frequently overexpressed across cancers and has been associated with tumor progression, poor prognosis, and therapy resistance. Here, we identify CD155 as a modulator of HER2-targeted monoclonal antibody efficacy. Analysis of clinical datasets revealed that high CD155 expression correlates with overall, progression-free, and disease-specific survival in breast cancer, and has potential as a predictive biomarker for anti-HER2 therapy. Mechanistically, CD155 co-localizes with HER2 at the tumor cell membrane and modulates HER2-dependent signaling, including AKT phosphorylation and receptor clustering. Genetic or antibody-mediated loss of CD155 significantly impaired trastuzumab-mediated cytotoxicity in vitro and abolished therapeutic efficacy in both primary and metastatic HER2-positive breast cancer models in vivo , without altering HER2 expression. Moreover, CD155 depletion reduced CD8⁺ T cell infiltration, highlighting its dual role in modulating HER2 receptor biology and shaping the tumor immune microenvironment. Collectively, these findings position CD155 as a determinant of trastuzumab efficacy and a promising biomarker to guide patient stratification and optimize therapeutic outcomes in HER2-positive breast cancer.