Mast cells suppress glioblastoma progression via endoplasmic reticulum stress.

AIMS: Mast cells (MCs) are the major infiltrating immune cells in glioblastoma (GBM) and have been implicated in tumor development; however, their role and underlying mechanisms in GBM progression remain unclear. This study aimed to characterize the distribution of MCs infiltration in GBM, the functional role of MCs in GBM progression, and the associated regulatory mechanisms. METHODS: First, we used the CIBERSORT algorithm to determine the distribution of MCs in GBM based on TCGA data, followed by validation using clinical GBM tissue samples. R language packages were used to assess the prognostic impact of MCs on patients with GBM. Subsequently, in vitro and in vivo experiments were performed to determine the effects of MCs on the GBM phenotype. Next, high-throughput RNA sequencing was performed on GBM cells treated with or without MCs to screen for differentially expressed genes. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway analyses were performed to identify key signaling pathways involved in MCs-mediated GBM regulation. Finally, we validated the critical regulatory role of this pathway in MC-mediated GBM apoptosis using transmission electron microscopy for ultrastructure, CCK-8 assay for viability, Western blotting and immunofluorescence for gene expression and regulatory relationships, and flow cytometry for apoptosis. RESULTS: We observed that the distribution of activated and resting MCs differed markedly in GBM. Moreover, pharmacological activation of MCs with C48/80 limited the growth and induced apoptosis of GBM cells in vitro and suppressed tumor growth in vivo. GO and KEGG enrichment analyses revealed that many of the top-ranked pathways were associated with immune responses, among which the classical osteoclast differentiation pathway was among the most prominent. Further pathway analysis and biological validation demonstrated that endoplasmic reticulum stress (ERS) is a key apoptotic pathway through which MCs suppress GBM progression. CONCLUSIONS: This study reveals that MCs predominantly infiltrate GBM tissue in a resting state and that pharmacological activation with C48/80 can induce ERS in GBM cells to suppress tumor progression. These findings are important to understand the anti-tumor role of MCs against GBM proliferation and to assess the potential response of GBM to MCs-targeted immunotherapy.