Improving immunotherapy via tumor vessel normalization by blocking endothelial cell glycolysis

Traditional anti-angiogenesis strategies destroy tumor vessels. Their success is restricted by toxicity and resistance. The need for new anti-angiogenic strategies with fundamental distinct mechanisms is timely. An alternative therapeutic paradigm is tumor vessel normalization (TVN). By healing disorganized vessels, TVN improves perfusion and oxygenation, tightens the leaky vascular wall, thus reducing metastasis and enhancing chemotherapy delivery and responses. Recent studies showed that haplodeficiency of the glycolytic activator PFKFB3 in endothelial cells or treatment with the PFKFB3 inhibitor 3PO induces TVN, reduces metastasis and improves the delivery of and response to cisplatin. Here, we propose to broaden this concept to anti-cancer immunotherapy. Given the emerging importance of immunotherapy, we will investigate whether TVN induced by targeting EC glycolysis also improves intratumoral delivery and activation of immune cells. Moreover, we will evaluate whether TVN affects the metabolism of cancer cells and whether targeting these metabolic drivers enhances the vulnerability of cancer cells to immunotherapy. Integration of 3 emerging fields, include endothelial cells (ECs) metabolism, anti-cancer therapy and the novel, tumor vessel normalization (TVN) strategy, may improve the overall success of current immunotherapy