Reprogramming tumor vasculature: Integrating normalization biology with vascularized tumor-on-chip models

Abnormal tumor vasculature is a hallmark of the tumor microenvironment that promotes hypoxia, therapeutic resistance, and disease progression while limiting the delivery of anticancer therapy. Although early anti-angiogenic therapies were designed to starve tumors by eliminating their blood supply, excessive vessel pruning often aggravated hypoxia and selected for more aggressive phenotypes. These observations led to the concept of vascular normalization, whereby judicious modulation of angiogenic signaling transiently restores vessel structure and function, improving perfusion, oxygenation, drug delivery, and anti-tumor immunity. In this review, we discuss the mechanisms governing tumor vessel formation, maturation, and dysfunction, and examine therapeutic strategies aimed at normalizing the tumor vasculature. We further highlight the major challenges limiting clinical translation, including the transient and heterogeneous nature of the normalization window, adaptive resistance mechanisms, and the lack of robust tools for longitudinal monitoring. We then integrate vascular normalization biology with vascularized tumor-on-chip platforms, examining how key features of the tumor microenvironment, including tissue architecture, extracellular matrix remodeling, hemodynamic forces, metabolic gradients, and multicellular interactions, can be recreated and quantitatively monitored. We critically evaluate how engineering design, biomaterial selection, vascularization strategies, perfusion, and integrated sensing influence the ability of these platforms to capture vascular normalization and therapeutic responses. By linking the hallmarks of vascular normalization to measurable on-chip phenotypes, vascularized tumor-on-chip systems provide controlled frameworks for investigating resistance mechanisms, optimizing treatment timing, and advancing precision oncology. However, challenges related to physiological fidelity, standardization, scalability, and clinical validation continue to limit their broader translation.