Targeting HIF-2α in glioblastoma reshapes the immune infiltrate and enhances response to immune checkpoint blockade

Article Article scientifique Article Targeting HIF-2α in glioblastoma reshapes the immune infiltrate and enhances response to immune checkpoint blockade eng 2025-03-17 2025-03-17 author Espinoza Rojas Felipe Ignacio Translational Research Centre in Oncohaematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Swiss Cancer Center Léman, Geneva, Lausanne, Switzerland. 933775 author Tankov Stoyan Translational Research Centre in Oncohaematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Swiss Cancer Center Léman, Geneva, Lausanne, Switzerland. 888058 Département de médecine (DEMED) author Chliate Sylvie Translational Research Centre in Oncohaematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Swiss Cancer Center Léman, Geneva, Lausanne, Switzerland. 127714 Département des neurosciences cliniques (OTONO) author Pereira Couto Joana 0000-0001-6413-4145 Translational Research Centre in Oncohaematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Swiss Cancer Center Léman, Geneva, Lausanne, Switzerland. 901381 Département de pathologie et immunologie (PATIM) author Marinari Eliana Translational Research Centre in Oncohaematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Swiss Cancer Center Léman, Geneva, Lausanne, Switzerland.,Agora Cancer Research Center, Lausanne, Switzerland. 841772 Département de médecine (DEMED) author Vermeil Thibaud Alban Arnaud Translational Research Centre in Oncohaematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Swiss Cancer Center Léman, Geneva, Lausanne, Switzerland. 928804 author Lecoultre Marc 0000-0001-8003-3934 Translational Research Centre in Oncohaematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Swiss Cancer Center Léman, Geneva, Lausanne, Switzerland. 863097 author El Harane Nadia Translational Research Centre in Oncohaematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Swiss Cancer Center Léman, Geneva, Lausanne, Switzerland. 956447 Département de médecine (DEMED) author Dutoit Vallotton Valérie 0000-0002-3469-4237 Translational Research Centre in Oncohaematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Swiss Cancer Center Léman, Geneva, Lausanne, Switzerland.,Agora Cancer Research Center, Lausanne, Switzerland. 668630 Département de médecine (DEMED) author Migliorini Denis Translational Research Centre in Oncohaematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Swiss Cancer Center Léman, Geneva, Lausanne, Switzerland.,Agora Cancer Research Center, Lausanne, Switzerland. 838158 Département de médecine (DEMED) author Walker Paul Richard 0000-0001-8999-6366 Translational Research Centre in Oncohaematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. paul.walker@unige.ch.,Swiss Cancer Center Léman, Geneva, Lausanne, Switzerland. paul.walker@unige.ch. 104900 Département de médecine (DEMED) 119 10.1007/s00018-025-05642-8 40095115 1420-682X PMC11914682 https://link.springer.com/article/10.1007/s00018-025-05642-8 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-2α emerging as a potential regulator of tumor progression. However, its role in GBM immunosuppression remains unknown. Here, we investigate HIF-2α and the use of the HIF-2α 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-2α inhibition alleviated the immunosuppressive TME and synergized with immune checkpoint blockade (ICB) using αPD-1 and αTIM-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-2α in microglia impeded their polarization towards a pro-tumoral M2-like profile, and its inhibition impaired Treg migration. Our results show that targeting HIF-2α 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-2α inhibitors should be explored not only in malignancies with defects in the HIF-2α axis, but also in those exhibiting an immunosuppressive TME that limits immunotherapy responsiveness. Brain tumors Glioma HIF-2 Hypoxia inducible factor Immune checkpoint inhibitors Immunotherapy Microglia Treg Tumor microenvironment Tumor-associated macrophage Glioblastoma / immunology Glioblastoma / pathology Glioblastoma / drug therapy Glioblastoma / metabolism Animals Basic Helix-Loop-Helix Transcription Factors / metabolism Basic Helix-Loop-Helix Transcription Factors / genetics Basic Helix-Loop-Helix Transcription Factors / antagonists & inhibitors Basic Helix-Loop-Helix Transcription Factors / immunology Mice Tumor Microenvironment / immunology Tumor Microenvironment / drug effects Immune Checkpoint Inhibitors / pharmacology Immune Checkpoint Inhibitors / therapeutic use Brain Neoplasms / immunology Brain Neoplasms / pathology Brain Neoplasms / drug therapy Brain Neoplasms / metabolism Humans Mice, Inbred C57BL T-Lymphocytes, Regulatory / immunology T-Lymphocytes, Regulatory / metabolism Cell Line, Tumor Microglia / metabolism Microglia / immunology Microglia / drug effects Macrophages / immunology Macrophages / metabolism Macrophages / drug effects Indans Sulfones Dewey 616 56 Département de médecine 221 false 1310 Tumeurs cérébrales 1016 401 Immunobiologie des tumeurs du cerveau 669 27 Immunothérapie des cancers 42 Cellular and molecular life sciences 82 1 ff5f8122-f71a-41f7-b001-2665a40fb755 Article (Published version) Public EspinozaCellMolLifeSci2025.pdf 6653992 application/pdf CC BY-4.0 8ce65464bc71af82f918bfa5c1165942a82a4fca4101dd7cb4b875345ba67eed 448e01ae-ad2f-4119-af0a-4287c2c05b30 Supplemental data Public 18_2025_5642_MOESM1_ESM.docx 10253225 application/vnd.openxmlformats-officedocument.wordprocessingml.document 51e5cdc3900bdebb2b6d029ea34ff01232ae35ffb0e1442c7f30d8b9dfa4a291 c3ae4105-6ac4-4595-8e26-18a89166a55e Supplemental data Public 18_2025_5642_MOESM2_ESM.xlsx 11401 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 99d1137679bd3e42163a1f3457d8c781a893dafccdb0b1c027311328dba057f6 9416e089-9d0d-4424-a9a3-52aee64d04c9 Supplemental data Public 18_2025_5642_MOESM3_ESM.xlsx 6075401 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 35e7111dda6ab3061aa9203023e390ab6c600dff9f9442722883297bb0fc242b 2ba1b838-01dd-4d38-8d5a-58ba985388c6 Supplemental data Public 18_2025_5642_MOESM4_ESM.xlsx 4755999 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet df97dd35b5c949b601c1516614e77824a1a86725126a73a09b708a6d0b1de560 f516b94f-5a90-4dba-a61e-347e04c8d275 Supplemental data Public 18_2025_5642_MOESM5_ESM.xlsx 3820311 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet da83740fdf53a9bd6bf1983eddef2c7dfa9e5e51564ca9c8ec83e7b2878f2bfc 41c6a487-de61-4a67-bc01-3b32126ebfcc Supplemental data Public 18_2025_5642_MOESM6_ESM.xlsx 17635396 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 866ae94abf396fec8b36610311fc789713c542a6029746bd23561d31a66df8df c5f8cf5d-6505-412f-9828-71cf1f6f976a Supplemental data Public 18_2025_5642_MOESM7_ESM.xlsx 21093 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet ad977aac4b04c3bda707c2fa20b4bb84360e28ce02712990f84c7e59c0a5d293 76dabb79-8548-4fd1-928e-b1f777127434 Supplemental data Public 18_2025_5642_MOESM8_ESM.xlsx 3946356 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 460b9905900ed2153117c28ea61abb4a5aa15cbf23830b54bb0c530b4452979a openAccess Faculté de médecine / Section de médecine clinique / Département de médecine

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Targeting HIF-2α in glioblastoma reshapes the immune infiltrate and enhances response to immune checkpoint blockade	Cellular and molecular life sciences			2025	189	122

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