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

作者：Xuefei Liu, Jun Tan, Chun Wei Wu, Guanyin Huang, Yixin Cheng, Jianyang Hu, Binyu Zhang, Mao Zhao, Boxi Zhao, Jingru Lian, Shuqian Zheng, Lin Zeng, Meng Xu, Yang Xu, Shan Zeng, Hao Yu, Hui Yang, Zhixiang Zuo, Chuanyu Liu, Weineng Feng, Weinan Guo, Chunying Li, Sai-Lan Liu, Qing Liu, Feiqiu Wen, X P Hong · 发表于：Cancer Discovery · 年份：2026 · DOI：10.1158/2159-8290.cd-25-1663 · 被引用次数：4 · 研究领域：RNA modifications and cancer、Lung Cancer Research Studies、Brain Metastases and Treatment

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/P...