Targeting angiogenesis: Lessons from 25 years of normalizing tumor vasculature

Tumors acquire blood vessels primarily via sprouting angiogenesis and co-option of pre-existing host vasculature, but also via intussusception, vasculogenesis from bone-marrow-derived progenitors, vascular mimicry, and endothelial transdifferentiation.The abnormal structure and function of these vessels, resulting from an imbalance between pro-and anti-angiogenic signaling as well as from the physical forces, impair the delivery and efficacy of therapeutics.We review the evolving narrative of targeting angiogenesis from starving tumors to vascular normalization as a therapeutic principle and highlight recent spatial-omics revelations and the emerging role of neural, microbial, hormonal, and chronological factors.We elaborate on the molecular mechanisms of tumor vessel formation, how dysfunctional vessels cause an abnormal tumor microenvironment characterized by hypoxia, low pH, elevated fluid pressure, and immunosuppression, and how vascular normalization enhances the delivery and efficacy of various therapies, including immunotherapies, and has formed the basis of emerging strategies and novel therapeutic agents to improve patient outcomes.immunotherapy, spawning a number of studies on combining anti-VEGF/R treatment with immunotherapy in preclinical models and cancer patients.15,17,34 • Late 2010s -Immune-checkpoint blockers shown to normalize tumor vasculature via secretion of anti-angiogenic molecule gamma-interferon by CD4/8 T cells.[35][36][37] • 2020 -Anti-VEGF plus immune-checkpoint blockade becomes first-line therapy in RCC and HCC.38,39 • Early 2020s -Endothelial metabolism and mechanical vessel compression identified as regulators of vascular dysfunction, leading to new strategies for vascular normalization.40,41 • 2022-present -Vascular normalization shown to improve the outcome of CAR T cell therapy, leading to the development of CAR T cells that produce anti-VEGF sFv antibody.42 PD-(L)1×VEGF bispecific antibodies demonstrate clinical efficacy, advancing next-generation vascular targeting.43