Copper transporters promote the malignant progression of glioblastoma by regulating the immunosuppressive tumour microenvironment via the SLC31A1-WNT5A axis

BACKGROUND: The prognosis for patients with glioblastoma (GBM) remains extremely poor, a challenge largely attributable to the complex nature of its malignant progression and an insufficient understanding of the dynamic plasticity and spatial heterogeneity inherent in the tumour microenvironment during invasion. In recent years, copper has emerged as a trace element of considerable interest due to its implicated role in tumour initiation and progression. This study was therefore designed to systematically investigate the involvement of copper transporter genes in the malignant evolution of glioma. METHODS: To achieve a comprehensive evaluation, we integrated bulk RNA transcriptome, single-cell RNA sequencing, and spatial transcriptomic data derived from glioblastoma specimens. Our analytical approach focused on delineating the expression patterns and functional significance of copper transporter genes, with particular emphasis on their spatial distribution and association with key microenvironmental features such as hypoxia. Furthermore, we employed a panel of ten machine learning algorithms to interrogate copper transport-related signature genes, leading to the construction of a prognostic risk model. RESULTS: Our analysis identified that the copper transporter SLC31A1 is aberrantly overexpressed in glioma and displays marked spatial heterogeneity, which correlates strongly with the hypoxic niche within the tumour. An elevated copper transport status was predictive of poorer patient outcomes and was closely linked to the upregulation of oncogenic pathways and the immunosuppressive remodelling of the tumour microenvironment. At the cellular level, heightened copper transport activity was predominantly observed in myeloid cells and was intimately associated with the immunosuppressive polarisation of macrophages and microglia. Mechanistically, we found that a hypoxic microenvironment promotes the acquisition of an active copper transport state in these cells, which in turn may drive malignant progression in tumour cells through enhanced secretion of the WNT5A ligand. The prognostic model, constructed from six key genes, demonstrated robust stability and predictive performance across glioma cohorts of varying grades. CONCLUSIONS: By providing a multidimensional evaluation of copper transporter dynamics, this study offers a theoretical foundation for optimising glioblastoma treatment strategies through targeting the copper metabolism-tumour axis. The findings underscore the therapeutic potential of modulating the WNT5A ligand and highlight the importance of considering both metabolic and immunological factors in future therapeutic interventions.