Inducing vascular normalization: A promising strategy for immunotherapy

In solid tumors, the vasculature is highly abnormal in structure and function, resulting in the formation of an immunosuppressive tumor microenvironment by limiting immune cells infiltration into tumors. Vascular normalization is receiving much attention as an alternative strategy to anti-angiogenic therapy, and its potential therapeutic targets include signaling pathways, angiogenesis-related genes, and metabolic pathways. Endothelial cells play an important role in the formation of blood vessel structure and function, and their metabolic processes drive blood vessel sprouting in parallel with the control of genetic signals in cancer. The feedback loop between vascular normalization and immunotherapy has been discussed extensively in many reviews. In this review, we summarize the impact of aberrant tumor vascular structure and function on drug delivery, metastasis, and anti-tumor immune responses. In addition, we present evidences for the mutual regulation of immune vasculature. Based on the importance of endothelial metabolism in controlling angiogenesis, we elucidate the crosstalk between endothelial cells and immune cells from the perspective of metabolic pathways and propose that targeting abnormal endothelial metabolism to achieve vascular normalization can be an alternative strategy for cancer treatment, which provides a new theoretical basis for future research on the combination of vascular normalization and immunotherapy.