American Association for Cancer Research
cd-22-0455_supplemental_figure_s5_suppsf5.pdf (666.68 kB)

Supplemental Figure S5 from Targeting Microglial Metabolic Rewiring Synergizes with Immune-Checkpoint Blockade Therapy for Glioblastoma

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journal contribution
posted on 2023-04-04, 15:41 authored by Zengpanpan Ye, Xiaolin Ai, Kailin Yang, Zhengnan Yang, Fan Fei, Xiaoling Liao, Zhixin Qiu, Ryan C. Gimple, Huairui Yuan, Hao Huang, Yanqiu Gong, Chaoxin Xiao, Jing Yue, Liang Huang, Olivier Saulnier, Wei Wang, Peidong Zhang, Lunzhi Dai, Xin Wang, Xiuxing Wang, Young Ha Ahn, Chao You, Jianguo Xu, Xiaoxiao Wan, Michael D. Taylor, Linjie Zhao, Jeremy N. Rich, Shengtao Zhou

Supplemental Figure S5 describes that genetic knockout of Nr4a2 in microglia reverses immunosuppressive state.


National Natural Science Foundation of China (NSFC)

National Key Research and Development Program of China (NKPs)

Sichuan Province Science and Technology Support Program (Science and Technology Project of Sichuan)

Direct Scientific Research Grants from West China Second Hospital, Sichuan University

Foundation for the National Institutes of Health (FNIH)

Computational Genomic Epidemiology of Cancer (CoGEC) Program at Case Comprehensive Cancer Center

Young Investigator Award in Glioblastoma from ASCO Conquer Cancer Foundation

RSNA Research Resident Grant



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. 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

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