Vascular Endothelial Growth Factor/Angiopoietin‐2 Bispecific Antibody‐Induced Vascular Normalization: From Basic Mechanisms to Therapeutic Applications in Breast Cancer

Abnormal tumor vasculature is a hallmark of breast cancer, characterized by tortuous, hyperpermeable, and poorly perfused vessels that contribute to hypoxia, therapeutic resistance, and immune exclusion. Vascular endothelial growth factor (VEGF) and angiopoietin-2 (ANG2) are central drivers of these vascular abnormalities, with VEGF promoting endothelial proliferation and leakiness, and ANG2 destabilizing vessel structure by antagonizing Tie2-mediated pericyte coverage. Monotherapies targeting VEGF provide only transient vascular normalization, as compensatory ANG2 upregulation limits efficacy. Dual inhibition of VEGF and ANG2 via bispecific antibodies offers a mechanistically grounded strategy to achieve more durable vascular normalization. Preclinical studies demonstrate that VEGF/ANG2 bispecific antibodies enhance pericyte coverage, reduce leakage, improve perfusion, alleviate hypoxia, increase intratumoral drug delivery, and promote immune cell infiltration, thereby suppressing tumor growth and metastasis. Early clinical trials indicate acceptable safety profiles and biologic activity, with greatest therapeutic potential observed in combination with chemotherapy, immune checkpoint inhibitors, and radiotherapy. Ongoing translational studies are focused on optimizing dosing, identifying predictive biomarkers, and overcoming resistance mechanisms. This review summarizes the biology of VEGF and ANG2 signaling, mechanisms of vascular normalization, preclinical and clinical evidence of VEGF/ANG2 bispecific antibodies, and current and future therapeutic applications in breast cancer, highlighting their potential to enhance multimodal treatment efficacy and improve patient outcomes.