Targeting Microglial Metabolic Rewiring Synergizes with Immune-Checkpoint Blockade Therapy for Glioblastoma

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 WangYoung Ha Ahn, Chao You, Jianguo Xu, Xiaoxiao Wan, Michael D. Taylor, Linjie Zhao, Jeremy N. Rich, Shengtao Zhou

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)974-1001
Number of pages28
JournalCancer discovery
Volume13
Issue number4
DOIs
StatePublished - Apr 1 2023

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