GPNMB Drives Brain Metastasis by Sculpting a Pathologic Endothelial-Immune Interactome PMID: 41973996

ADC Targets in Oncology

2026-04-10

GPNMB Drives Brain Metastasis by Sculpting a Pathologic Endothelial-Immune Interactome

Cancer Discov. 2026 Jul 1;16(7):1382-1411. doi: 10.1158/2159-8290.CD-25-1663.

Xuefei Liu ^# ¹ ² , Jun Tan ^# ³ ⁴ , Chun Wu ^# ¹ ⁵ , Guanyin Huang ^# ¹ , Yixin Cheng ^# ⁶ , Jianyang Hu ¹ , Binyu Zhang ¹ , Mao Zhao ⁷ , Boxi Zhao ¹ , Jingru Lian ¹ , Shuqian Zheng ¹ , Lin Zeng ⁸ , Meng Xu ⁹ , Yang Xu ¹⁰ , Shan Zeng ¹¹ , Hao Yu ¹² ¹³ , Hui Yang ⁸ , Zhixiang Zuo ¹⁴ , Chuanyu Liu ¹⁵ ¹⁶ , Weineng Feng ¹⁷ , Weinan Guo ⁷ , Chunying Li ⁷ , Sai-Lan Liu ⁵ , Qing Liu ³ ⁴ , Feiqiu Wen ² , Xin Hong ¹ ¹⁸ ¹⁹

Affiliations

1. Department of Biochemistry, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
2. Department of Hematology and Oncology, Shenzhen Children's Hospital and School of Medicine, Southern University of Science and Technology, Shenzhen, China.
3. Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
4. National Clinical Research Center for Geriatric Disease, Xiangya Hospital, Central South University, Changsha, China.
5. State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
6. Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
7. Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
8. Research Center for Bionic Sensing and Intelligence, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
9. Foshan Key Laboratory of Precision Therapy in Oncology and Neurology, Department of Genitourinary Oncology, The First People's Hospital of Foshan (The Affiliated Foshan Hospital of Southern University of Science and Technology), Foshan, Guangdong, China.
10. Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
11. Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.
12. Institute of Biomedical and Health Engineering, Shen Zhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
13. Key Laboratory of Biomedical Imaging Science and System, Chinese Academy of Sciences, Shenzhen, China.
14. State Key Laboratory of Oncology in South China, Cancer Center, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China.
15. State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China.
16. Shenzhen Proof-of-Concept Center of Digital Cytopathology, BGI Research, Shenzhen, China.
17. Foshan Key Laboratory of Precision Therapy in Oncology and Neurology, Department of Pulmonary Oncology, The First People's Hospital of Foshan (The Affiliated Foshan Hospital of Southern University of Science and Technology), Foshan, Guangdong, China.
18. Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, China.
19. Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Southern University of Science and Technology, Shenzhen, China.
# Contributed equally.

Abstract

Brain metastasis remains a devastating disease with dismal prognosis. How circulating tumor cells (CTC) penetrate the blood-brain barrier (BBB) and reprogram the brain microenvironment remains unclear. Using spatially resolved multi-omics profiling of CTCs and brain metastases, integrated with experimental and clinical analyses, we identified glycoprotein nonmetastatic melanoma protein B (GPNMB) as a CTC-secreted driver of vascular disruption and brain colonization. CBX3 upregulation induced GPNMB expression, which bound endothelial EGFR, triggering CBL-mediated ubiquitination and degradation. Attenuated EGFR signaling suppressed FTO and disrupted endothelial junctions via YTHDF2-dependent TJP1 m6A methylation. Remarkably, GPNMB-induced BBB remodeling promoted immune infiltration via the CXCL12-CXCR4 axis and induced time-course-dependent T-cell exhaustion within the brain microenvironment. Clinically, elevated CBX3+GPNMB+ CTCs and plasma CXCL12 were significantly associated with brain metastasis progression in lung Cancer and melanoma. Therapeutically, dual blockade of GPNMB and PD1 enhanced anti-brain metastasis efficacy in mice, unveiling GPNMB as a promising target for precision immunotherapy.

Significance: GPNMB is a CTC-secreted driver of BBB disruption and brain colonization via the CBX3-GPNMB-EGFR-FTO-TJP1 axis. GPNMB-induced BBB remodeling promotes CXCL12-CXCR4-mediated immune infiltration and enhances T-cell exhaustion, sensitizing brain metastasis tumors to GPNMB/PD1 dual blockade. CBX3+GPNMB+ CTCs and plasma CXCL12 may serve as noninvasive biomarkers for brain metastasis management.