Reprogramming tumor angiogenesis in breast cancer: Mechanisms, challenges, and future directions

Angiogenesis serves as a central hallmark of breast cancer progression by driving the formation of a dysfunctional vascular network that sustains tumor growth, enables metabolic adaptation, and facilitates metastasis. Hypoxia within the tumor microenvironment (TME) stabilizes hypoxia-inducible factor-1α (HIF-1α), that transcriptionally activates key pro-angiogenic mediators, including vascular endothelial growth factor (VEGF) and angiopoietins (ANGPT). Concurrently, stromal and immune constituents of the TME, particularly cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), potently augment angiogenesis through the secretion of cytokines, growth factors, and extracellular matrix-remodeling enzymes. These mediators promote endothelial cell activation, increase vascular permeability, and facilitate immune suppression. The VEGF/VEGFR signaling axis serves as a master regulator, orchestrating endothelial cell proliferation, migration, survival, and neovascularization. Although anti-angiogenic agents such as the VEGF-neutralizing monoclonal antibody bevacizumab have demonstrated clinical efficacy, responses are frequently transient owing to intrinsic and acquired resistance, intratumoral vascular heterogeneity, and compensatory activation of alternative angiogenic pathways. Consequently, contemporary therapeutic approaches prioritize rational combination regimens integrating anti-angiogenic agents with chemotherapy, immunotherapy, or radiotherapy to induce vascular normalization, enhance drug penetration, and potentiate antitumor immunity. Targeting the TME, including stromal and immune components, together with bioactive phytochemicals, possessing anti-angiogenic and immunomodulatory properties, has emerged as a promising strategy. This review integrates current knowledge on tumor-endothelial crosstalk, hypoxia- and inflammation-driven angiogenic signatures such as VEGF, miR-20a, and ANGPTL4, while evaluating emerging modalities, including microRNA-based interventions, nanoparticle delivery, and TME reprogramming to overcome resistance and enhance the precision and durability of anti-angiogenic therapies in breast cancer.