Malignant meningiomas have a high mortality rate and short survival time and currently have no effective treatment. In our study, proteomics analysis was performed to identify highly expressed proteins as therapeutic targets in malignant meningiomas. Cell Counting Kit-8 (CCK-8) assays were performed to verify the effect of LB-100 on the growth of malignant meningiomas. In addition, immunoblotting was used to verify the expression of B7-H3 and phosphorylation of STAT1 (Tyr701) in tissues and cells. Our results show that STAT1 and CD276 (B7-H3) regulated by PP2A were enriched in GO_IMMUNE_EFFECTOR_PROCESS and GO_REGULATION_OF_IMMUNE_SYSTEM_PROCESS. The immunotherapy target protein B7-H3 was confirmed to be upregulated in malignant meningiomas compared with meningothelial (p = 0.0001) and fibroblastic (p = 0.0046) meningiomas. In vitro, the PP2A inhibitor LB-100 suppressed the growth and invasion of malignant meningioma cells. Notably, the PP2A inhibitor LB-100 increased the phosphorylation of STAT1, thereby increasing the expression of the immune checkpoint protein B7-H3 in malignant meningioma cells in vitro. In conclusion, B7-H3 was found to be upregulated in malignant meningiomas. The PP2A inhibitor LB-100 increased the phosphorylation of STAT1 and B7-H3 expression, which could increase the sensitivity of malignant meningiomas to B7-H3 targeted immunotherapy.

Introduction: Glioblastoma (GBM) is the most malignant form of glioma and has a poor median survival time. Fibroblast activation protein alpha (FAP) is a dual‐specificity serine protease that is strongly associated with the development and progression of human carcinomas. However, relatively little is known about the function of FAP and its potential as a therapeutic target in GBMs.Aims: In this study, we aimed to explore the role of FAP in GBM through a series of experiments and to evaluate the therapeutic effect of PT100, a small molecule inhibitor of FAP, on GBM.Results: Increased FAP expression was associated with poor survival in glioma. In vitro, FAP knockdown inhibited the process of EMT and caused a decrease in the number of M2 macrophages. In vivo, PT100 was confirmed to suppress the progression of GBMs significantly.Conclusions: FAP could serve as a biomarker and novel therapeutic target for the treatment of GBM and that PT100 is a promising drug for the treatment of GBM.

Glioblastoma (GBM) is one of the most lethal adult brain tumors with limited effective therapeutic options. Immunotherapy targeting B7-H3 ( CD276 ) has shown promising efficacy in the treatment of gliomas. However, the response to this treatment varies among glioma patients due to individual differences. It’s necessary to find an effective strategy to improve the efficacy of targeting B7-H3 immunotherapy for nonresponders. In this study, we demonstrated a strong correlation between aurora kinase A ( AURKA ) and CD276 expression in glioma tissue samples. Additionally, both AURKA knockdown and overexpression resulted in parallel changes in B7-H3 expression levels in glioma cells. Mechanistically, AURKA elevated B7-H3 expression by promoting epidermal growth factor receptor (EGFR) phosphorylation, which was validated in glioma cell lines and primary GBM cells. What’s more, the combination of AURKA inhibitor (alisertib) and anti–B7-H3 antibody markedly reduced tumor size and promoted CD8 ⁺ T cell infiltration and activation in mouse orthotopic syngeneic glioma models. To our knowledge, this study is the first to demonstrate AURKA-mediated B7-H3 upregulation in glioma cells; moreover, it proposes a promising therapeutic strategy combining the AURKA inhibitor alisertib with B7-H3–specific blocking mAbs.

Background: Diffuse midline glioma (DMG) is an aggressive pediatric brain tumor with limited treatment options. Although natural killer (NK) cell-based immunotherapy is promising, its efficacy remains limited, necessitating strategies to enhance NK cell cytotoxicity. Histone deacetylase (HDAC) inhibition demonstrate potential to enhance NK-mediated killing. However, the combination of HDAC inhibitors and NK cell therapy for DMG remains unexplored. Methods: Patient-derived DMG cell lines and orthotopic mouse models were used to evaluate the effects of the class I HDAC inhibitor MS-275 on cytotoxicity. NK cell-mediated lysis was measured using both luciferase and calcein AM-based assays. The downstream signaling pathways affected by MS-275 were investigated via RNA-seq, CUT&Tag assay, RT‒qPCR, and chromatin immunoprecipitation with qPCR. Results: Based on bioinformatic analysis, class I HDACs are identified as therapeutic targets in DMG. The corresponding HDAC inhibitor, MS-275 upregulated NK cell-mediated cytotoxicity pathway through GSEA analysis. Pretreating DMG cells with MS-275 elevated NK cell ligand gene expression and enhanced NK cell-induced lysis. In addition to NK-activating ligands, MS-275 elevated the NK-inhibitory ligand HLA-E, thereby enhancing the efficacy of immunotherapies targeting the NKG2A–HLA-E axis. Mechanistically, MS-275 increased HLA-E expression by promoting STAT3 acetylation at lysine 685. Combining MS-275 with NK cell therapy and blockade of the NKG2A–HLA-E axis extended overall survival in orthotopic mouse models. Conclusions: This study is the first to demonstrate that HDAC inhibition enhances NK cell-mediated cytotoxicity in DMG. Combining HDAC inhibition with NK cell therapy represents a promising therapeutic strategy for treating DMG by targeting NKG2A–HLA-E axis.

Background: Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft tissue sarcoma characterized by high recurrence and poor prognosis, necessitating the search for novel therapeutic targets and strategies. This study investigated the expression of mitochondrial translocator protein (TSPO) in MPNST and its role in regulating ferroptosis.Methods: TSPO expression was analyzed in adjacent non-tumor tissues, benign neurofibromas, and malignant tissues using real-time PCR, western blotting, immunohistochemistry staining. Expression levels of classic ferroptosis markers, including AKR1C1 and FTH1 were assessed. Ferroptosis was evaluated by measuring cell viability, ferroptosis marker levels, and intracellular Fe²⁺ and reactive oxygen species (ROS) levels. Oxidized phospholipid profiles of wild-types and TSPO knockdown MPNST cells were determined using liquid chromatography-mass spectrometry. The potential role of GPX4 in mediating TSPO’s effect on ferroptosis was investigated in vitro.Results: Compared with adjacent non-tumor tissues and benign neurofibromas, TSPO expression was significantly lower in MPNST specimens. Notably, TSPO expression positively correlated with the classic ferroptosis markers AKR1C1 and FTH1. TSPO-knockdown MPNST cells exhibited significant resistance to ferroptotic cell death. Additionally, biochemical characterization indicated that TSPO deficiency decreased intracellular Fe²⁺ and ROS. Furthermore, oxidized phospholipids were remarkably reduced in TSPO-knockdown cells. TSPO enriches cellular oxidized phospholipids by downregulating GPX4-GSH antioxidant pathway. Furthermore, GPX4 is elevated in malignant tumors compared to benign specimens and negatively correlated with TSPO expression in clinical tumor specimens.Conclusion: Our findings revealed that TSPO deficiency inhibited ferroptosis in MPNST cells by upregulating GPX4 antioxidant pathway, suggesting that mitochondrial TSPO-GPX4-ferroptosis axis may be a promising therapeutic target for improving the outcomes of patients with MPNST.