Gliomas are malignant tumors in the central nervous system. Cuproptosis is a newly discovered cell death mechanism targeting lipoylated tricarboxylic acid cycle proteins. Previous studies have found that cuproptosis participates in tumor progression, but its role in gliomas is still elusive. Here, we systematically explored the bulk-tumor and single-cell transcriptome data to reveal its role in gliomas. The cuproptosis activity score (CuAS) was constructed based on cuproptosis-related genes, and machine learning techniques validated the score stability. High CuAS gliomas were more likely to have a poor prognosis and an aggressive mesenchymal (MES) subtype. Subsequently, the SCENIC algorithm predicted 20 CuAS-related transcription factors (TFs) in gliomas. Function enrichment and microenvironment analyses found that CuAS was associated with tumor immune infiltration. Accordingly, intercellular communications between neoplasm and immunity were explored by the R package "Cellchat". Five signaling pathways and 8 ligand-receptor pairs including ICAM1, ITGAX, ITGB2, ANXA1-FRR1, and the like, were identified to suggest how cuproptosis activity connected neoplastic and immune cells. Critically, 13 potential drugs targeting high CuAs gliomas were predicted according to the CTRP and PRISM databases, including oligomycin A, dihydroartemisinin, and others. Taken together, cuproptosis is involved in glioma aggressiveness, neoplasm-immune interactions, and may be used to assist in drug selection.

Glioma is a fatal primary brain tumor. Improved glioma treatment effectiveness depends on a better understanding of its underlying mechanisms. Glioblastoma (GBM), was classified as high-grade glioma with the most lethality and therapeutic resistance. Herein, we reported LINC00978 overexpressed in high-grade gliomas. Down-regulation of LINC00978 in glioblastoma cells inhibited cell proliferation, invasion, migration, and induced apoptosis. In vivo experiments confirmed that the CamK-A siRNA of LINC00978 could effectively inhibit the proliferation of glioblastoma cells. The main pathway and genes regulated by LINC00978 were detected using RNA sequencing to elucidate the molecular mechanism. The results suggest that LINC00978 regulates the expression of genes related to metabolic pathways, including aldo-keto reductase family 1 member B (AKR1B1), which mediates the cytotoxicity of 2-deoxyglucose. LINC00978 positively regulated AKR1B1 expression, and 2-deoxyglucose induced AKR1B1 expression via a LINC00978-dependent mechanism. This research has revealed that LINC00978 promotes the sensitivity of glioblastoma cells to 2DG. LINC00978 is highly expressed in most high-grade glioma patients. Thus, understanding the anticancer mechanism identified in this study may contribute to treating the majority of glioma patients. This study clarified the function and molecular mechanism of LINC00978 in glioblastoma and provided a study basis for LINC00978 to guide the clinical treatment of glioblastoma.

Purpose Tertiary lymphoid structures (TLS) are pivotal modulators of anti-tumor immunity in solid tumors; however, their clinical significance in glioblastoma (GBM) remains under-characterized. This study aimed to evaluate the correlation between TLS spatial-quantitative characteristics and survival outcomes in GBM patients to refine prognostic stratification and immunotherapy optimization. Methods A retrospective analysis was conducted on 62 patients with isocitrate dehydrogenase (IDH)-wildtype GBM treated at our institution (2016 – 2023). TLSs were identified via H&E and CD3 / CD20 immunohistochemical (IHC) staining. A grading system was established based on the quantity and spatial distribution (intratumoral vs. peritumoral) of TLS. Survival outcomes were assessed using Kaplan–Meier curves and multivariate Cox regression models to identify independent prognostic factors. Results TLSs were present in 58.1% of the cohort. Survival analysis revealed that TLS status, grading, and extent of resection significantly correlated with overall survival (OS; P < 0.05). Notably, higher TLS grades, particularly those characterized by intratumoral localization (Score 3), were associated with significantly prolonged OS. Multivariate analysis confirmed that TLS grading is an independent favorable prognostic factor for OS in this GBM cohort. Conclusion The proposed TLS grading system provides a potential prognostic stratification tool for GBM that warrants external validation. These findings emphasize the role of TLSs in the GBM immune microenvironment and offer a potential biomarker for selecting patients likely to benefit from intensified immunotherapeutic interventions.