Anti-angiogenic Therapy at the Vascular Crossroads: Tumor Vessel Normalization, Excessive Pruning, and Systemic Vascular Toxicity.

Tumor angiogenesis contributes to tumor growth, metastasis, and treatment resistance, but the newly formed vessels are often structurally abnormal and functionally inefficient. Antiangiogenic therapy, particularly inhibition of Vascular Endothelial Growth Factor (VEGF) signaling, is now used in the treatment of multiple cancers. Its vascular effects depend strongly on the extent of angiogenic inhibition. Moderate inhibition may temporarily improve the structure and function of abnormal tumor vessels. This vascular normalization can improve perfusion, oxygenation, immune cell infiltration, and drug delivery in selected tumor types and treatment settings. More extensive vessel pruning can have the opposite effect, reducing perfusion, worsening hypoxia, and favoring adaptive resistance. VEGF inhibition also affects normal vessels because physiological angiogenic signaling is required for endothelial homeostasis. Disruption of this signaling contributes to hypertension, thromboembolism, renal injury, cardiovascular complications, and cerebrovascular events. In this narrative review, the mechanisms that shape tumor vascular remodeling and compare the vascular effects of anti-angiogenic and other vascular-modulating anticancer therapies in tumors and normal tissues are examined. Particular attention is given to the distinction between tumor-vessel normalization and vascular injury in normal tissues, as well as treatment scheduling, combination strategies, targeted delivery, and vascular-response biomarkers.