Targeting tumor vascularization: promising strategies for vascular normalization

Tumor recurrence after the clinical cure of tumor often results from the presence of an abnormal microenvironment, including an aberrant vasculature. The tumor microenvironment is rich in pro-angiogenic factors but lacks pro-maturation factors. Pro-angiogenic conditions in the tumor microenvironment, such as hypoxia, are double-edged swords, promoting both the repair of normal tissues and the development of an abnormal blood vessel network. The coexistence of perfusion and hypoxic zones and uneven blood vessel distribution in tumor tissues profoundly influence tumor deterioration, recurrence, and metastasis. Traditional anti-angiogenic therapies have shown limited efficacy, and promote drug resistance, and even metastasis. In contrast, vascular normalization therapy induces a more physiological-like state, leading to better outcomes and fewer side effects. Vascular normalization entails modifying the tumor vascular system to improve tumor oxygenation and substance transport, thereby contributing to improving the efficacy of radiotherapy, chemotherapy, and immunotherapy. This review mainly focuses on the process of tumor vascularization; potential therapeutic targets, including cells, metabolism, signaling pathways, and angiogenesis-related genes; and possible strategies to normalize blood vessels through regulating tumor vessel generation, the development of tumor vessels, and blood vessel fusion and pruning.