Abstract
BACKGROUND: Glioblastoma (GBM) is the most common intracranial malignancy in adults, and traditional treatments such as surgery, chemotherapy, and radiotherapy have shown limited improvements in patient prognosis. While immunotherapy has transformed treatment outcomes for many cancers, GBM patients often exhibit resistance due to the tumor's unique immunosuppressive microenvironment, resulting in poor prognosis. The mucosa-associated lymphoid tissue translocation gene 1 (MALT1) has been implicated in the activation of nuclear factor kappa-B and the promotion of cancer cell proliferation and migration. Inhibiting MALT1 has been shown to reduce the mesenchymal phenotype of GBM. Thus, understanding the role of MALT1 in GBM's immunosuppressive microenvironment is crucial. MATERIALS AND METHODS: In this study, we analyzed RNA-seq data from 169 GBM patients obtained from The Cancer Genome Atlas database, categorizing them into MALT1_High and MALT1_Low groups based on MALT1 expression levels. We quantified the enrichment levels of 29 immune signatures for each patient in both the groups. We then identified differentially expressed immune genes and used these to develop an immune prognostic signature (IPS) through Least Absolute Shrinkage and Selection Operator Cox regression analysis. Furthermore, we validated the role of MALT1 in GBM through MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), scratch assays, and small interfering RNA knockdown experiments. In addition, we tested the effects of promising MALT1 inhibitors identified through computer-aided technologies. RESULTS: Our analysis revealed that PDYN, a gene not previously associated with GBM prognosis, could serve as a potential target. Using a three-gene IPS, we created a predictive nomogram model to assess the prognosis of GBM patients. The validation experiments confirmed that MALT1 plays a significant role in promoting GBM cell proliferation, migration, and invasion. In addition, the computer-aided identification of MALT1 inhibitors demonstrated their potential to inhibit GBM progression. CONCLUSION: This study explored the role of MALT1 in GBM's immunosuppressive microenvironment, developed a novel MALT1-related prognostic model, and identified potential targeted therapies for GBM, providing new avenues for therapeutic intervention.