VEGF Signaling and Targeted Therapies in Cancer: Molecular Mechanisms, Clinical Applications, Resistance, and Cardiorenal Toxicities

Vascular endothelial growth factor (VEGF) signaling is a central regulator of tumor angiogenesis and a major therapeutic target in oncology. VEGF-neutralizing agents and VEGF receptor tyrosine kinase inhibitors (VEGFR-TKIs) confer clinical benefit in multiple solid malignancies, but resistance and cardiovascular and renal toxicities can limit durable treatment. This review summarizes VEGF ligands, VEGF receptors, and the principal signaling mechanisms relevant to angiogenesis and lymphangiogenesis, with emphasis on VEGFR2 and VEGFR3 biology. We then examine established VEGF-targeted therapies, representative clinical evidence for VEGFR-TKIs, mechanisms of therapeutic resistance, and VEGF inhibitor-associated hypertension, endothelial dysfunction, proteinuria, and kidney injury. Particular attention is given to strategies for improving the therapeutic index of VEGF pathway inhibition, including risk assessment and toxicity monitoring, immunotherapy combinations, and emerging mechanism-based approaches. Modulation of the epoxyeicosatrienoic acid (EET)/soluble epoxide hydrolase axis is discussed as a promising experimental strategy for cardiorenal protection; however, current support is predominantly preclinical and requires clinical validation. Integrating tumor vascular biology with mechanisms of normal vascular and renal homeostasis may facilitate safer and more effective VEGF-directed cancer therapy.