Microenvironmental regulation and remodeling of breast cancer angiogenesis: from basic mechanisms to clinical therapeutic implications

Angiogenesis, the formation of new blood vessels, is a pivotal process in breast cancer (BC) progression and metastasis, intricately regulated by complex interactions within the tumor microenvironment (TME). While the vascular endothelial growth factor (VEGF) pathway represents a cornerstone of these pro-angiogenic mechanisms, resistance to anti-VEGF therapies is common, underscoring the involvement of alternative pathways. Key insights reveal that hypoxia, metabolic reprogramming, and stromal components including cancer-associated fibroblasts (CAFs), cancer-associated adipocytes (CAAs) and immune cells, cooperate to drive aberrant angiogenesis and treatment resistance. This review synthesizes emerging evidence on the multifaceted regulation of angiogenesis by endothelial cells (ECs), pericytes, immune cells, and stromal components in shaping the angiogenic landscape, and discusses innovative therapeutic strategies. These include hypoxia-targeted agents, immune modulation, and combination therapies that co-target compensatory pathways. We emphasize that overcoming resistance requires integrated approaches that remodel the TME rather than solely inhibiting VEGF. Finally, we highlight ongoing clinical trials and translational opportunities aimed at improving outcomes and reducing metastasis in breast cancer patients.