Evolution of vascular normalization strategies: from anti-angiogenesis to remodeling the tumor microenvironment

Although anti-angiogenic therapy has been widely used in the treatment of solid tumors, angiogenesis inhibition alone frequently induces acquired resistance and exacerbates tumor hypoxia, paradoxically promoting tumor progression. The concept of tumor vascular normalization has offered a new perspective to address this dilemma, shifting the therapeutic strategy from “vessel destruction” to “vessel repair.” This review systematically elucidates the pathological characteristics of aberrant tumor vasculature and the cascading responses driven by these abnormalities. We summarize the molecular regulatory networks underlying vascular normalization across multiple dimensions, including VEGF signaling, hypoxia-inducible factors, extracellular matrix remodeling, metabolic reprogramming, and immune cell coordination. On this basis, this review further explores how vascular normalization systematically reshapes the tumor immune microenvironment by alleviating immunosuppression, promoting T cell infiltration, supporting an IFN-γ-mediated positive feedback loop, and coordinating with tertiary lymphoid structure formation. Finally, we dissect the multicellular interaction networks among tumor cells, endothelial cells, pericytes, and immune cells, and propose future directions including the vascular-immune dual-biomarker system and the targeting of pericyte phenotypic switching. This review provides a systematic framework for understanding the synergistic mechanisms linking vascular normalization and immune reprogramming, and lays a foundation for optimizing combination therapeutic strategies.