Recent advances in cancer treatment highlight the potential of natural medicines to target the tumor vascular microenvironment, offering a novel strategy to inhibit tumor growth and metastasis. Unlike conventional therapies that directly target tumor cells, natural compounds focus on normalizing tumor vasculature and inhibiting pathological angiogenesis, crucial processes in cancer progression. This innovative approach holds promise in enhancing anti-cancer therapies while minimizing side effects.

The tumor vascular microenvironment plays a pivotal role in cancer development. Tumor blood vessels are often irregular, immature, and leaky, which leads to poor blood perfusion, increased interstitial pressure, and hypoxia within the tumor. These abnormal conditions create a conducive environment for tumor invasion and metastasis. As tumors grow, they actively recruit blood vessels by secreting angiogenic factors like VEGF and FGF, resulting in an unorganized vascular network that fails to deliver therapeutic agents efficiently.

Natural medicines have emerged as promising agents to normalize tumor vasculature. Certain phenolic compounds such as resveratrol and curcumin demonstrate anti-angiogenic properties by inhibiting VEGF signaling and reducing the production of matrix metalloproteinases (MMPs). Resveratrol, derived from plants, has shown potential in suppressing endothelial cell (EC) proliferation and reducing the formation of abnormal blood vessels. Similarly, curcumin, known for its anti-inflammatory properties, blocks VEGF and IL-8 signaling pathways, inhibiting tumor angiogenesis and preventing cancer cell migration.

Moreover, alkaloids like paclitaxel and colchicine inhibit tumor growth by disrupting microtubule dynamics in endothelial cells, effectively impairing blood vessel formation. Paclitaxel not only inhibits EC proliferation but also enhances apoptosis, thereby reducing vascular density within tumors. Colchicine, through its effect on microtubule stability, suppresses the formation of new blood vessels, limiting nutrient supply to the tumor.

Terpenoids such as ursolic acid and artesunate target signaling pathways linked to angiogenesis, including NF-κB and STAT3, reducing the proliferation of endothelial cells. By mitigating the expression of pro-angiogenic factors, these compounds contribute to vascular stabilization and improved tumor perfusion. Additionally, crustal oligosaccharides, derived from natural sources, show potential in enhancing vascular normalization by reducing endothelial permeability and promoting blood vessel integrity.

Incorporating natural medicines into cancer treatment strategies offers multiple advantages. These agents not only complement conventional therapies but also reduce toxicity by promoting vascular normalization. By stabilizing the tumor blood supply, they enhance the delivery of chemotherapeutic drugs, making treatments more effective. Furthermore, the use of natural compounds helps mitigate resistance mechanisms that often limit the efficacy of anti-angiogenic therapies.

As research progresses, the integration of natural medicines with existing oncological practices could significantly improve patient outcomes. By targeting the tumor vascular microenvironment, these therapies not only suppress tumor growth but also inhibit metastasis, offering a comprehensive approach to cancer management. The continued exploration of these compounds holds promise for developing more sustainable and less toxic cancer therapies.

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Reference
Yirui Lu, Zhiliang Guo, Hong Li, Jiao Wen, Xiaoyun Zhang, Xiumei Guan, Xiaodong Cui, Min Cheng, Natural medicines target tumor vascular microenvironment to inhibit tumor, Genes & Diseases, Volume 12, Issue 6, 2025, 101623, https://doi.org/10.1016/j.gendis.2025.101623

Funding
Weifang Science and Technology Development Projects (Shandong, China) 2023YX092