Functional vasculature in tumor organoids: Enabling precision medicine in oncology

Conventional in vitro models often inadequately replicate the intricate vascular networks of tumors, limiting their translational relevance. Recent advances in vascularized tumor organoids offer a transformative approach to modeling angiogenic mechanisms and tumor microenvironment (TME) dynamics with high fidelity. This review synthesizes current knowledge on the cellular and molecular regulators of tumor angiogenesis, emphasizing pivotal pathways such as vascular endothelial growth factor (VEGF), neurogenic locus notch homolog protein (Notch), and hypoxia-mediated signaling, and their implications for targeted therapies. We evaluate cutting-edge strategies for engineering vascularized organoids, including self-assembling systems, scaffold-guided patterning, microfluidic organ-on-chip platforms and host-derived vascularization approaches. These methods collectively enhance physiological mimicry through perfusable microvasculature and stromal-endothelial crosstalk. Despite these innovations, persistent challenges in organoid standardization, scalability, culture reproducibility, and immune compartment integration hinder their full potential in recapitulating the immunosuppressive TME. Additionally, while vascularized organoids present a promising platform for anti-angiogenic drug screening, translational discrepancies highlight the necessity for improved biomimetic design. Future research should prioritize the development of robust vascularization protocols, incorporation of multicellular TME components, and integration with high-throughput systems to enhance preclinical predictability. Addressing these limitations will position vascularized tumor organoids as indispensable tools for elucidating angiogenesis-dependent malignancy mechanisms and advancing precision oncology.