Glycoprotein nonmetastatic B as a pharmacological target in cancer: structural mechanisms, druggability, and therapeutic translation.
The malignant progression of cancer depends not only on oncogenic driver mutations but also on the adaptive rewiring of organelle stress responses that sustain cell survival under hostile tumor microenvironment (TME) conditions. Among these, the hijacking of lysosomal homeostasis has emerged as a critical vulnerability and a driver of therapeutic resistance. Glycoprotein nonmetastatic B (GPNMB), a highly glycosylated type I transmembrane protein predominantly localized to lysosomes, is robustly upregulated across multiple cancer types as an adaptive responder to lysosomal stress. In tumors, GPNMB drives proliferation, metastasis, and immune evasion by engaging multiple oncogenic signaling cascades, while simultaneously shaping an immunosuppressive TME through CD8+ T cell exhaustion and cytokine networks. Clinically, high GPNMB expression correlates with poor prognosis in breast cancer, hepatocellular carcinoma (HCC), lung cancer, glioblastoma (GBM), gastric cancer (GC), and osteosarcoma (OS), positioning it as both a prognostic biomarker and a therapeutic target. The GPNMB-directed antibody-drug conjugate (ADC) glembatumumab vedotin (GV) has demonstrated clinical activity in triple-negative breast cancer (TNBC) and melanoma, yet its efficacy remains constrained by target expression heterogeneity, the reliance on lysosomal trafficking for payload release, and dose-limiting toxicities. Emerging strategies, including bispecific antibodies, immunotoxins, and senolytic elimination of GPNMB-high damaged cells, are expanding the therapeutic landscape. This review dissects the molecular mechanisms, pathological roles, and evolving clinical applications of GPNMB in cancer, highlighting current challenges and future directions for precision oncology.