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Life Sci."],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Glioblastoma (GBM) is an aggressive primary brain tumor with dismal clinical prognosis and resistance to current therapies. GBM progression is facilitated by the tumor microenvironment (TME), with an immune infiltrate dominated by tumor-associated microglia\/macrophages (TAMs) and regulatory T cells (Tregs). The TME is also characterized by hypoxia and the expression of hypoxia-inducible factors (HIFs), with HIF-2\u03b1 emerging as a potential regulator of tumor progression. However, its role in GBM immunosuppression remains unknown. Here, we investigate HIF-2\u03b1 and the use of the HIF-2\u03b1 inhibitor PT2385 to modulate the TME in the immunocompetent GL261 mouse GBM model. PT2385 administration in vivo decreased tumor volume and prolonged survival of tumor-bearing mice, without affecting GL261 viability in vitro. Notably, HIF-2\u03b1 inhibition alleviated the immunosuppressive TME and synergized with immune checkpoint blockade (ICB) using \u03b1PD-1 and \u03b1TIM-3 antibodies to promote long-term survival. Comprehensive analysis of the immune infiltrate through single-cell RNA sequencing and flow cytometry revealed that combining PT2385 with ICB reduced numbers of pro-tumoral macrophages and Tregs while increasing numbers of microglia, with a corresponding transcriptional modulation towards an anti-tumoral profile of these TAMs. In vitro, deletion of HIF-2\u03b1 in microglia impeded their polarization towards a pro-tumoral M2-like profile, and its inhibition impaired Treg migration. Our results show that targeting HIF-2\u03b1 can switch an immunosuppressive TME towards one that favors a robust and sustained response to ICB based immunotherapy. These findings establish that clinically relevant HIF-2\u03b1 inhibitors should be explored not only in malignancies with defects in the HIF-2\u03b1 axis, but also in those exhibiting an immunosuppressive TME that limits immunotherapy responsiveness.<\/jats:p>","DOI":"10.1007\/s00018-025-05642-8","type":"journal-article","created":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T08:46:33Z","timestamp":1742201193000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Targeting HIF-2\u03b1 in glioblastoma reshapes the immune infiltrate and enhances response to immune checkpoint blockade"],"prefix":"10.1007","volume":"82","author":[{"given":"Felipe I.","family":"Espinoza","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stoyan","family":"Tankov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvie","family":"Chliate","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joana","family":"Pereira Couto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliana","family":"Marinari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thibaud","family":"Vermeil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Lecoultre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"El Harane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9rie","family":"Dutoit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis","family":"Migliorini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8999-6366","authenticated-orcid":false,"given":"Paul R.","family":"Walker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,17]]},"reference":[{"issue":"5","key":"5642_CR1","doi-asserted-by":"publisher","first-page":"381","DOI":"10.3322\/caac.21693","volume":"71","author":"KD Miller","year":"2021","unstructured":"Miller KD et al (2021) Brain and other central nervous system tumor statistics, 2021. 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