Beyond inhibition: harnessing the DRD2–VEGF-A feedback loop for precision anti-angiogenesis therapy in cancer

Current anti-angiogenic therapies using vascular endothelial growth factor-A/vascular endothelial growth factor receptor-2 (VEGF-A/VEGFR2) inhibitors lack dynamic biomarkers that can facilitate patient selection and optimize dosing; this can lead to suboptimal and unsatisfactory outcomes and significant toxicities. To address this, we propose a paradigm shift leveraging the dopamine D2 receptor (DRD2)/VEGF-A paracrine feedback loop. In the tumor microenvironment, VEGF-A selectively induces endothelial DRD2 expression through specific transcriptional mechanisms – a molecular signature that is absent in quiescent normal vasculature. DRD2 activation serves as a potent, tumor-specific vascular brake on VEGFR2 phosphorylation and paracellular permeability. By utilizing FDA-approved DRD2 agonists as functional probes, clinicians can implement a dopaminergic challenge to identify windows of maximal VEGF-dependency via dynamic imaging. This approach transforms anti-angiogenic interventions from empirical into a precision theranostic platform, enabling real-time assessment of tumor VEGF-dependency and rational treatment selection that maximizes efficacy while minimizing toxicity.