biostudies-literatureYe ZComputational Genomic Epidemiology of Cancer (CoGEC) Program at Case Comprehensive Cancer CenterSichuan Province Science and Technology Support ProgramDirect Scientific Research Grants from West China Second Hospital, Sichuan UniversityFoundation for the National Institutes of HealthNational Natural Science Foundation of ChinaNCI NIH HHSNINDS NIH HHSRSNA Research Resident GrantNational Key Research and Development Program of ChinaYoung Investigator Award in Glioblastoma from ASCO Conquer Cancer Foundation974-1001https://www.ebi.ac.uk/biostudies/studies/S-EPMC10073346biostudies-literatureUnknown13(4)Glioblastoma (GBM) constitutes the most lethal primary brain tumor for which immunotherapy has provided limited benefit. The unique brain immune landscape is reflected in a complex tumor immune microenvironment (TIME) in GBM. Here, single-cell sequencing of the GBM TIME revealed that microglia were under severe oxidative stress, which induced nuclear receptor subfamily 4 group A member 2 (NR4A2)-dependent transcriptional activity in microglia. Heterozygous Nr4a2 (Nr4a2+/-) or CX3CR1+ myeloid cell-specific Nr4a2 (Nr4a2fl/flCx3cr1Cre) genetic targeting reshaped microglia plasticity in vivo by reducing alternatively activated microglia and enhancing antigen presentation capacity for CD8+ T cells in GBM. In microglia, NR4A2 activated squalene monooxygenase (SQLE) to dysregulate cholesterol homeostasis. Pharmacologic NR4A2 inhibition attenuated the protumorigenic TIME, and targeting the NR4A2 or SQLE enhanced the therapeutic efficacy of immune-checkpoint blockade in vivo. Collectively, oxidative stress promotes tumor growth through NR4A2-SQLE activity in microglia, informing novel immune therapy paradigms in brain cancer.<h4>Significance</h4>Metabolic reprogramming of microglia in GBM informs synergistic vulnerabilities for immune-checkpoint blockade therapy in this immunologically cold brain tumor. This article is highlighted in the In This Issue feature, p. 799.Cancer discoveryTargeting Microglial Metabolic Rewiring Synergizes with Immune-Checkpoint Blockade Therapy for Glioblastoma.PMC10073346KS021R01 CA2686342019YFH0144R01 CA238662K1907T32CA0941862018YFA0109200CA23866281822034T32 CA094186CA268634R01 NS1034342022YFA110660081821002R35 CA19771882103127NA81773119CA197718822732552017YFA01068008220288922ZYZYTS0070NS103434Huang HHuang LWan XGong YYe ZYue JZhang PQiu ZZhao LFei FWang WWang XAi XAhn YHTaylor MDYang KLiao XRich JNZhou SSaulnier OYuan HXu JGimple RCYang ZDai LYou CXiao CfalseTargeting Microglial Metabolic Rewiring Synergizes with Immune-Checkpoint Blockade Therapy for Glioblastoma.Glioblastoma (GBM) constitutes the most lethal primary brain tumor for which immunotherapy has provided limited benefit. The unique brain immune landscape is reflected in a complex tumor immune microenvironment (TIME) in GBM. Here, single-cell sequencing of the GBM TIME revealed that microglia were under severe oxidative stress, which induced nuclear receptor subfamily 4 group A member 2 (NR4A2)-dependent transcriptional activity in microglia. Heterozygous Nr4a2 (Nr4a2+/-) or CX3CR1+ myeloid cell-specific Nr4a2 (Nr4a2fl/flCx3cr1Cre) genetic targeting reshaped microglia plasticity in vivo by reducing alternatively activated microglia and enhancing antigen presentation capacity for CD8+ T cells in GBM. In microglia, NR4A2 activated squalene monooxygenase (SQLE) to dysregulate cholesterol homeostasis. Pharmacologic NR4A2 inhibition attenuated the protumorigenic TIME, and targeting the NR4A2 or SQLE enhanced the therapeutic efficacy of immune-checkpoint blockade in vivo. Collectively, oxidative stress promotes tumor growth through NR4A2-SQLE activity in microglia, informing novel immune therapy paradigms in brain cancer.<h4>Significance</h4>Metabolic reprogramming of microglia in GBM informs synergistic vulnerabilities for immune-checkpoint blockade therapy in this immunologically cold brain tumor. This article is highlighted in the In This Issue feature, p. 799.2023-01-01T00:00:00Z2023 Apr2026-05-28T18:06:20.604Z2025-02-18T23:59:23.184ZS-EPMC100733463664956410.1158/2159-8290.CD-22-045510.1158/2159-8290.cd-22-0455