Macrophage-mediated brain-bone marrow crosstalk promotes chronic stress-induced glioma growth PMID: 42314665

ADC Targets in Oncology

2026-04-10

Macrophage-mediated brain-bone marrow crosstalk promotes chronic stress-induced glioma growth

Cancer Cell. 2026 Jun 18:S1535-6108(26)00263-1. doi: 10.1016/j.ccell.2026.05.018.

Zhengnan Yang ¹ , Jingtian Zhou ² , Fan Fei ³ , Bohao Zheng ⁴ , Sophie Xin Yang ⁵ , Thomas M Pearce ⁶ , Peidong Zhang ¹ , Liang Huang ¹ , Jing Yue ¹ , Qiuhong Shen ¹ , Yiwei Du ¹ , Xiaoling Liao ³ , Siyu Cheng ⁵ , Li Li ⁷ , Jian Liang ¹ , Luyao Liu ¹ , Xiaoxiao Wan ⁸ , Michael D Taylor ⁹ , Joseph R Ecker ¹⁰ , Shengtao Zhou ¹¹ , Jeremy N Rich ¹² , Linjie Zhao ¹³

Affiliations

1. Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Department of Neurosurgery, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, P.R. China.
2. Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA; Arc Institute, Palo Alto, CA, USA.
3. Department of Neurosurgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, P.R. China.
4. Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Department of Neurosurgery, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, P.R. China; Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China.
5. Business Administration of Business School, Sichuan University, Chengdu, P.R. China.
6. Department of Pathology, Division of Neuropathology, University of Pittsburgh, Pittsburgh, PA, USA.
7. Department of Medical Records Management, West China Second University Hospital, Sichuan University, Chengdu, P.R. China.
8. Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
9. Pediatric Neuro-Oncology Research Program, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA; Division of Neurosurgery, Texas Children's Hospital, One Baylor Plaza, Houston, TX, USA.
10. Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA; Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA, USA.
11. Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Department of Neurosurgery, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, P.R. China; Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, Chengdu, P.R. China. Electronic address: [email protected].
12. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. Electronic address: [email protected].
13. Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Department of Neurosurgery, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, P.R. China. Electronic address: [email protected].

Abstract

Stress is associated with increased Cancer morbidity and mortality. Here, we show that chronic stress accelerates glioma growth and reduces survival of tumor-bearing mice. Integrated multi-omics analysis of syngeneic glioma samples reveals stress-induced CD45⁺CD11b⁺C5aR1⁺ macrophages, termed stress-associated macrophages (SAMs). Using parabiosis experiments in mice, we demonstrate that SAMs are derived from bone marrow monocytes. Stress-activated sympathetic nerve promotes the differentiation of ADRB2⁺ bone marrow monocytes into SAMs, which can be antagonized by selective ablation of catecholaminergic nerves. Conditional knockout of C5ar1 in macrophages, or pharmacologic C5aR inhibition, reduces SAMs and attenuates stress-induced glioma tumor growth in vivo. SAMs exhibit elevated CD36 expression, leading to excessive intracellular lipid accumulation and peroxidization, dampening their phagocytotic capacity. SAMs abundance correlates with self-reported stress levels and portended prognosis in glioma patients. Collectively, these findings suggest that stress reprograms tumor immune microenvironment by inducing molecularly distinguished monocyte-derived macrophages, revealing potential opportunities for immune-based Cancer therapies.

Keywords

brain-bone marrow crosstalk; glioma; macrophage; stress.