GPNMB Drives Brain Metastasis by Sculpting a Pathological Endothelial-Immune Interactome
Cancer Discovery, 2026
Liu X., Tan J., Wu C., Huang G., Cheng Y., Hu J., Zhang B., Zhao M., Zhao B., Lian J., Zheng S., Zeng L., Xu M., Xu Y., Zeng S., Yu H., Yang H., Zuo Z., Liu C., Feng W., Guo W., Li C., Liu S., Liu Q., Wen F., Hong X.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Oncology | Pathophysiology | Plasma |  Olink Target 96 |
Abstract
Brain metastases (BM) remain a devastating disease with dismal prognosis. How circulating tumor cells (CTCs) penetrate the blood brain barrier (BBB) and reprogram the brain microenvironment remain unclear. Using spatially resolved multi-omic profiling of CTCs and brain metastases, integrated with experimental and clinical analyses, we identified Glycoprotein Non-Metastatic 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 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 BM progression in lung cancer and melanoma. Therapeutically, dual blockade of GPNMB and PD1 enhanced anti-BM efficacy in mice, unveiling GPNMB as a promising target for precision immunotherapy.