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Hypoxia plays a pivotal role in the TME through hypoxia-inducible factor 1-alpha (HIF-1\u03b1) which upregulates vascular endothelial growth factor (VEGF). VEGF, an angiogenesis stimulator, suppresses tumor immunity by inhibiting the maturation of dendritic cells, and induces immunosuppressive cells such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells. HIF-1\u03b1 directly induces immune checkpoint molecules. VEGF\/VEGF receptor (VEGFR)-targeted therapy as a cancer treatment has not only anti-angiogenic effects, but also immune-supportive effects. Anti-angiogenic therapy has the potential to change the immunological \u201ccold tumors\u201d into the \u201chot tumors\u201d. Glioblastoma (GB) is a hypervascular tumor with high VEGF expression which leads to development of an immuno suppressive TME. Therefore, in the last decade, several combination immunotherapies with anti-angiogenic agents have been developed for numerous tumors including GBs. In particular, combination therapy with an immune checkpoint inhibitor and VEGF\/VEGFR-targeted therapy has been suggested as a synergic treatment strategy that may show favorable changes in the TME. In this article, we discuss the cross talk among immunosuppressive cells exposed to VEGF in the hypoxic TME of GBs. Current efficient combination strategies using VEGF\/VEGFR-targeted therapy are reviewed and proposed as novel cancer treatments.<\/jats:p>","DOI":"10.1007\/s12032-019-1329-2","type":"journal-article","created":{"date-parts":[[2019,11,11]],"date-time":"2019-11-11T12:03:21Z","timestamp":1573473801000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":210,"title":["The role of vascular endothelial growth factor in the hypoxic and immunosuppressive tumor microenvironment: perspectives for therapeutic implications"],"prefix":"10.1007","volume":"37","author":[{"given":"Ryota","family":"Tamura","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6474-6317","authenticated-orcid":false,"given":"Toshihide","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuharu","family":"Akasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Murayama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazunari","family":"Yoshida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hikaru","family":"Sasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,11,11]]},"reference":[{"key":"1329_CR1","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.tig.2008.10.012","volume":"25","author":"K Polyak","year":"2009","unstructured":"Polyak K, Haviv I, Campbell IG. 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