Search Results (25)

Neuropeptide Y [NPY; encoded by the NPY gene] is a widely expressed 36-amino-acid neuropeptide that regulates neuronal function, vascular regulation, and immune regulation; its role in glioblastoma [GBM] remains incompletely characterized. We performed an integrative in silico multi-scale transcriptomic analysis combining bulk RNA-sequencing of IDH-wildtype GBM [n = 169] and lower-grade glioma [n = 510] surgical resections from TCGA, normal cortical tissue from GTEx [n = 207], and four independent GEO validation cohorts of surgical GBM and non-tumor brain specimens [GSE4290, GSE50161, GSE131928 scRNA-seq of ~20,426 cells from 28 patients, and GSE194329 10X Visium spatial transcriptomics from five patients], along with survival modeling, pathway enrichment, single-cell RNA sequencing, spatial transcriptomics, and cell–cell communication analysis. NPY and its principal receptor, NPY1R, were significantly downregulated in GBM, while genes associated with hypoxia, angiogenesis, invasion, and immune suppression were upregulated. Single-cell analysis showed that NPY-axis transcript expression was elevated in neural progenitor-like populations. In contrast, hypoxia and metabolic programs were concentrated in mesenchymal tumors and stromal compartments, indicating distinct cellular contexts. Spatial analysis revealed a weak and heterogeneous relationship between NPY and hypoxia signatures, with substantial inter-patient variability and no significant global spatial cross-correlation. These findings indicate that loss of NPY signaling is a consistent feature of GBM and is associated with hypoxia-driven tumor states, while the spatial relationship between NPY and hypoxia appears weak, heterogeneous, and patient-specific. Full article

Background/Objectives: T cells within solid tumors often switch from a recirculating to a tissue-resident state, which may blunt antitumor activity, but the signal driving this switch in vivo remains unclear. We asked whether alterations in sphingosine-1-phosphate (S1P) signaling in tumor or the surrounding stromal cells are associated with T cell residency in glioblastoma (GBM). Methods: We analyzed five single-cell RNA-sequencing cohorts: three human glioma datasets, an in-house mouse CT2A glioblastoma cohort, and a human melanoma tumor-infiltrating lymphocyte cohort. T cell egress and tissue-residency programs, together with stromal S1P production and degradation, were scored per cell using curated gene modules. Cell-state contrasts were quantified as Cohen’s d, and sample-level coupling as Spearman ρ. Results: In human GBM, T cell residency programs were elevated in CD4+ helper and regulatory T cells in tumors compared with low-grade glioma controls. In mouse CT2A-derived GBM tumors, stromal S1P production correlated negatively with T cell residency across four independent stromal cell types. In human GBM microglia, S1P production was reduced compared with control microglia. The same CD8+ residency phenotype was replicated in CD3-sorted GBM tumor-infiltrating lymphocytes (TILs) and in melanoma TILs. Conclusions: A loss of stromal S1P production accompanies T cell tissue residency in GBM. Thus, stromal S1P metabolism is a candidate axis for modulating T cell recirculation and TIL biology in GBM. These findings are transcriptomic associations from single-cell RNA sequencing that do not directly measure S1P metabolite levels or signaling activity and will require functional and lipidomic validation. Full article

Background/Objectives: TGFB2 is the dominant TGF-β isoform in glioma, and isolated experimental studies have implicated it in immunosuppressive signaling; however, its prognostic value and systematic association with the tumor immune microenvironment across the diffuse glioma spectrum have not been comprehensively characterized in large clinical cohorts. Methods: A multi-cohort transcriptomic study was conducted using TCGA (n = 667) as discovery and CGGA (n = 404) as validation, integrating survival analysis, functional enrichment, immune deconvolution by ssGSEA and MCP-counter, immune checkpoint correlation, and TISCH2-based single-cell localization. Results: TGFB2 was consistently overexpressed in glioma relative to normal brain at both mRNA and protein levels, with expression highest in GBM (median 10.60 vs. 8.45 in LGG; p < 2.2 × 10⁻¹⁶) and increasing across WHO grade. High TGFB2 predicted worse overall survival in both cohorts (TCGA: 648 vs. 2907 days; CGGA: 863 vs. 3107 days; both p < 0.0001), with 3-year AUCs of 0.823 and 0.714, and retained independent prognostic significance in the CGGA multivariate model (HR = 1.343; p = 3.2 × 10⁻⁴). Hallmark GSEA identified consistent enrichment of interferon signaling, epithelial–mesenchymal transition, TNFα/NF-κB, and IL-6/JAK/STAT3 pathways. ssGSEA and MCP-counter concordantly demonstrated significantly expanded myeloid, monocytic, and stromal populations across both cohorts. TGFB2 correlated positively with PD-L1, TIM-3, ICOS (ρ = 0.449), IL2RA (ρ = 0.397), CTLA4 (ρ = 0.375), and TIGIT (ρ = 0.170) in TCGA, with all associations replicated in CGGA. Conclusions: TGFB2 is an adverse prognostic biomarker in diffuse glioma coupled to a myeloid-enriched, multi-checkpoint-activated tumor microenvironment, supporting its evaluation as a stratification biomarker in TGF-β/checkpoint combination immunotherapy trials. Full article

Gliomas remain among the most treatment-resistant malignancies of the central nervous system. Glioblastoma (GBM), the most aggressive adult-type diffuse glioma, is associated with persistently poor survival despite maximal safe resection followed by chemoradiation. Gliomas do not grow in isolation. Work over the past twenty years has dismantled the older tumor-centric view of glioma biology, replacing it with a model in which malignant cells operate within a tumor microenvironment (TME) composed of immune, vascular, stromal, and neural elements that together govern disease behavior. What makes the glioma TME so difficult to treat is not just its composition of immune cells, vasculature, stroma, and neurons, but the fact that these elements are arranged unevenly across the tumor. Different regions harbor different cellular mixtures and signaling environments, and, as a result, different vulnerabilities to therapy. Cytoreduction has not lost its importance, far from it. However, the same surgical window now also serves a different purpose; it lets the surgeon see which tissue is biologically dangerous rather than just visually abnormal, locate the true edge of infiltration, and get therapeutics past a blood–brain barrier (BBB) that has historically locked them out of the brain. This review examines two technology domains, including: (1) optical theranostics (5-aminolevulinic acid fluorescence-guided surgery, fluorescein-guided visualization, Raman spectroscopy, and stimulated Raman histology); and (2) blood–brain barrier disrupting technologies. The direction they collectively point toward is a version of glioma surgery that is guided less by anatomy and more by the biology of the tumor itself. Full article

Background: Gliomas are characterized by a high degree of molecular heterogeneity, which impairs the reproducibility of predictive biomarkers derived from bulk-based molecular profiling due to immune/stromal contamination of tumors and the high prevalence of the IDH mutation signature. Methods: In this study, we used MOFA+ to derive intrinsic molecular signatures from transcriptional, methylation, and genomic profiles of a cohort of 667 diffuse gliomas in the Cancer Genome Atlas database. Thereafter, factor scores were derived for two separate Chinese Glioma Genome Atlas batches (Batch 1, n = 325; Batch 2, n = 693) without any retraining on the model. The prognostic independence of identified molecular signatures was assessed using multivariable Cox regression adjusted for IDH mutation status and tumor purity; purity-residualized survival analyses; IDH-stratified Cox regression in each cohort; validation by concordance index against established molecular signatures; and survival extreme profiling. To characterize the biological significance of factor signatures, we projected gene set signatures corresponding to each factor signature onto a single-cell RNA-seq dataset of GBM (GSE131928). Results: MOFA+ identified 12 latent factors, of which a vascular–extracellular matrix (ECM) remodeling axis (Factor 1) explained the highest multi-omics variance (24.9%) and was the strongest independent prognostic factor. In multivariable Cox regression adjusting for IDH status and tumor purity, Factor 1 remained independently prognostic (HR = 1.67, 95% CI 1.27–2.20, p = 0.0002); in a fully-adjusted model additionally including age, WHO grade, MGMT methylation, and 1p/19q codeletion (plus radiotherapy and chemotherapy status in the CGGA cohorts), Factor 1 remained prognostic in both CGGA cohorts (CGGA1: HR = 1.50, p = 3.8 × 10⁻⁵; CGGA2: HR = 1.18, p = 0.003) but lost significance in TCGA (HR = 1.04, p = 0.83), consistent with the cohort-dependent magnitude reported in the IDH-stratified and meta-regression analyses below. Purity-residualized survival analysis showed negligible attenuation of the Factor 1 signal (raw HR = 3.57 vs. residualized HR = 3.72; concordance 96.5%). Within IDH-wildtype gliomas, Factor 1 was significant in both external validation cohorts (CGGA1: HR = 1.64, FDR = 4.6 × 10⁻⁶; CGGA2: HR = 1.20, FDR = 0.02), though the TCGA IDH-wildtype subgroup showed a trend that did not survive FDR correction (FDR = 0.060). All validation was performed without model retraining. Within IDH-mutant gliomas, Factor 1 was strongly prognostic in both CGGA cohorts but was not significant in TCGA (HR = 1.17, FDR = 0.33). These findings should therefore be interpreted as consistent in directionality across cohorts but not uniformly replicated at the FDR-adjusted significance threshold in the TCGA discovery dataset. Concordance index benchmarking on a matched subset (n = 503) showed Factor 1 achieved discrimination comparable to the Mesenchymal signature (C = 0.797 vs. 0.801; ΔC = −0.004) while outperforming four other established classifiers. Factor 1 consistently separated patients with extreme survival phenotypes (OS < 6 vs. >15 months) across all three cohorts (all log-rank p < 0.001). Projection onto a single-cell GBM atlas (GSE131928), supported by inferCNV-based malignant-cell classification, localized the Vascular–ECM program to malignant cells and the Immune–ECM axis to myeloid compartments. Conclusions: The Vascular–ECM axis is a consistent, prognostic program robust to purity adjustment for diffuse gliomas that remains relevant across IDH-defined subgroups in three independent datasets comprising 1685 patients. The Vascular–ECM axis is a reproducible, purity-robust prognostic program in diffuse glioma, with directionally consistent adverse effects across TCGA, CGGA Batch 1, and CGGA Batch 2 (pooled n = 1685). Given the strong co-loading of endothelial, ECM, and myeloid genes observed in the single-cell projection, Factor 1 is best interpreted as a vascular/ECM-associated tumor–microenvironment ecosystem program rather than a malignant-cell-autonomous signature. Its FDR-adjusted significance within IDH-stratified subgroups is cohort-dependent and robust in both CGGA cohorts but attenuated in the TCGA IDH-wildtype (FDR = 0.060) and TCGA IDH-mutant (FDR = 0.33) strata. The pooled signal should therefore be interpreted as evidence of a generalizable biological program rather than a uniformly replicated subgroup-specific biomarker. It is possible to calculate factor scores based on RNA sequencing alone using fixed loadings (Z = XWᵀ), which may have implications for future translational applications. All findings are correlative; a causal role for the Vascular–ECM program in glioma progression, invasion, or therapy resistance remains to be established through functional perturbation experiments. Full article

Synaptogenesis-related neuron–glioma interactions are increasingly recognized in glioma, yet it remains unclear whether routine H&E morphology can capture these programs and improve prognostic stratification. We integrated H&E whole-slide images, transcriptomes, and clinical data from 434 TCGA gliomas. Deep learning and quantitative pathology yielded an integrated histomorphologic feature set of 2678 features. Synaptogenesis-related activity was quantified using ssGSEA for ninety-eight synaptogenesis-related genes. In the training cohort, Spearman analysis identified 149 correlated histomorphologic features, which were refined to thirty-five by elastic net regularization. Seventeen prognostic candidates were entered into the MIME1 framework, and the most parsimonious model, Enet[0.1], retained fourteen non-zero-coefficient features to define the synaptogenesis-associated histomorphologic signature and construct the pathology-derived risk score (PRS). Multi-omic analyses, Human Protein Atlas validation, and single-nucleus RNA-seq were used to investigate the hub gene and its cellular context. PRS robustly stratified survival in both training and validation cohorts and remained an independent prognostic factor after adjustment for age and 2021 WHO CNS grade. High-risk tumors showed increased stromal and immune scores and enrichment of immune, adhesion, and phagosome-related pathways. EFNB2 emerged as the hub gene and was enriched in glioblastoma, and EFNB2-positive malignant cells displayed prominent communication with neurons, including EFNB2-EPHB1 signaling. Exploratory re-analysis of the myeloid compartment further showed that glioblastoma was enriched for suppressive TAM-like states relative to astrocytoma grade 2, supporting a shift toward a more tumor-associated and potentially immunosuppressive microenvironment. Routine H&E histomorphology can capture synaptogenesis-related molecular programs in glioma. The resulting PRS provides clinically relevant prognostic stratification, while EFNB2-positive malignant cells may represent a candidate hub for neuron–tumor communication within a remodeled tumor ecosystem. Full article

Astrocytes regulate key aspects of the neural microenvironment that can be co-opted by cancer to support tumor growth and invasion. Secreted protein acidic and rich in cysteine-like 1 (SPARCL1) is a matricellular glycoprotein expressed by astrocytes and stromal cells, whose expression varies across cancer types. While SPARCL1 is downregulated in many peripheral cancers, reports of its expression in gliomas, specifically glioblastoma (GBM), are inconsistent. The biological context underlying these divergent findings, and the role of SPARCL1 in GBM malignancy, remains unclear. Publicly available transcriptomic datasets from the Ivy Glioblastoma Atlas Project (Ivy GAP), GlioVis, and TCGA were analyzed to evaluate SPARCL1 expression across GBM cohorts. Spatially resolved gene expression data from Ivy GAP were used to assess SPARCL1 expression from defined tumor regions. Microarray and RNA sequencing datasets from GlioVis and TCGA, respectively, were used to assess SPARCL1 expression across whole-tumor samples. Spatial transcriptomics from Ivy GAP show SPARCL1 expression was upregulated along the leading edge and in infiltrating tumor regions. Microarray datasets showed greater SPARCL1 expression in tumors of astrocyte lineage as opposed to oligodendrocyte lineage. Bulk RNA sequencing showed high SPARCL1 expression in low-grade gliomas, which is consistent with astrocytic lineage, IDH mutation, and spatial averaging effects that might obscure regional associations. These findings demonstrate that SPARCL1 expression in GBM is shaped by tumor architecture, molecular classification, and microenvironment interactions. Enrichment of SPARCl1 at invasive tumor margins is consistent with prior studies linking SPARCL1 to neuron–glioma synapse formation and angiogenesis. Full article

Pregnancy-associated plasma protein A (PAPPA) is a metalloproteinase that regulates insulin-like growth factor availability via cleavage of IGF-binding proteins, yet its role in cancer remains incompletely understood. Using integrated public datasets, we systematically examined PAPPA expression, prognostic relevance, cellular localization, and stromal associations across multiple tumor types. PAPPA was reduced in several cancers and primarily localized to stromal cells, whereas in cholangiocarcinoma and thyroid carcinoma it was elevated and also detected in malignant cells. High PAPPA expression was associated with poorer overall survival in bladder, cervical, lung squamous, mesothelioma, pancreatic, and gastric cancers, but exhibited a protective effect in lower-grade glioma. In tumors with adverse prognosis, PAPPA strongly correlated with cancer-associated fibroblast (CAF) infiltration and CAF marker genes; however, multivariable Cox analyses indicated that PAPPA generally retained an independent prognostic factor, whereas CAF infiltration was mostly not independently associated with overall survival. Interestingly, in LGG, despite negative PAPPA–CAF correlations, multivariable analysis showed that PAPPA remained protective while CAF infiltration was associated with worse survival. Pathway analyses linked PAPPA-associated genes to proteoglycans in cancer and PI3K–AKT and RAS signaling. Collectively, these findings establish PAPPA as an independent prognostic factor across most cancers, while its expression frequently coincides with high CAF infiltration in select tumor types, highlighting the need for further investigation. Full article

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Since numerous studies highlight the significance of cholinergic system components in tumor development, acetylcholine (ACh) and the differential activation of its receptors could play a crucial role in GBM progression. The aim of this study was to test this hypothesis by assessing the relevance of the cholinergic system in GBM cells and their microenvironment. We analyzed bulk RNA-seq expression data using the TIMER2.0 web server, focusing on the impact of patient survival in relation to muscarinic receptors (CHRM) and neutrophil infiltration in low-grade glioma (LGG) and GBM. Our analysis revealed a marked decrease in survival associated with all CHRMs, particularly in LGG. Moreover, GBM showed higher neutrophil infiltration and reduced survival, especially in relation to CHRM3. These findings were validated in the U251 cell line and in human GBM tumor biopsies (GBM-b), which also displayed CHRM3 expression. Additionally, we show that GBM cells exposed to cholinergic stimulation exhibited increased vascular endothelial growth factor (VEGF), IL-8 production, and PD-L1 expression, while the VEGF increase was blocked by tiotropium (Tio), a CHRM3 antagonist. Similarly, polymorphonuclear cells from GBM patients (PMN-p) displayed increased PD-L1 expression and IL-8 production upon cholinergic stimulation. Finally, as we previously reported on the relevance of thymic stromal lymphopoietin (TSLP) in GBM pathophysiology, here, we found that TSLP upregulated CHRM3 expression. Our findings highlight the importance of the cholinergic system in the tumor microenvironment, where it may act directly on tumor cells or influence neutrophil physiology, thereby modulating tumor progression. Full article

Background: Human leukocyte antigen class I (HLA-I) plays a pivotal role in shaping anti-tumour immunity by influencing the functionality of T cells and natural killer (NK) cells within the tumour microenvironment. Methods: Here, we explored the transcriptional landscape of HLA-I molecules across various solid cancer transcriptomes from The Cancer Genome Atlas (TCGA) database and assessed the impact of HLA-I expression on the clinical significance of tumour-infiltrating CD56^dim and CD56^bright NK cells. Results: Our analysis revealed that high HLA-I expression correlated with reduced patient survival in the TCGA lower-grade glioma (LGG) cohort, with this association varying by histopathological subtype. We then estimated the relative abundance of 23 immune and stromal cell signatures in LGG transcriptomes using a cellular deconvolution approach, which revealed that LGG patients with low HLA-I expression and high CD56^dim NK cell abundance had better survival outcomes compared to those with high HLA-I expression and low CD56^dim NK cell abundance. Furthermore, HLA-I expression was positively correlated with various inhibitory NK cell receptors and negatively correlated with activating NK cell receptors, particularly those within the killer cell lectin-like receptor (KLR) gene family. High co-expression of HLA-E and NKG2A predicted poor survival outcomes in LGG patients, whereas low HLA-E and high NKG2C/E abundance predicted more favourable outcomes, suggesting a potential modulatory role of HLA-I on the tumour-infiltrating cytotoxic CD56^dim NK cell subset. Conclusions: Overall, our study unveils a potential role for deregulated HLA-I expression in modulating the clinical impact of glioma-infiltrating CD56^dim NK cells. These findings lay the foundation for future in-depth experimental studies to investigate the underlying mechanisms. Full article

Background: Firstly, 5-hydroxytryptamine G-protein-coupled receptors (HTGPCRs) are a family of 13 genes associated with cancer progression. Nevertheless, a comprehensive understanding of HTGPCRs in cancer remains largely lacking. Method: We tested the gene expression levels and prognostic values for the HTGPCRs in relation to pan-cancer. A subsequent analysis examined the relationships among HTGPCR expression and clinical characteristics, immune subtypes, stemness scores, tumor microenvironments (TMEs), single-cell analyses, and drug sensitivity. Result: A significant difference in HTGPCR expression was found between normal tissues and tumors. HTR1D/2C expressed higher levels in breast invasive carcinoma (BRCA), colon adenocarcinoma, and liver hepatocellular carcinoma. HTGPCR gene expression was correlated with prognosis in many cancers. HTR1D/2C were associated with poorer overall survival for head and neck squamous cell carcinoma. In addition, HTGPCR expression correlated significantly with the stemness scores of RNA and DNA, TMB, and MSI, as well as stromal and immune scores of pan-cancer patients. Additionally, the expression of HTR2A/2B/7 was correlated significantly with immune cells and immune checkpoint genes in a variety of cancers, such as BRCA, brain lower-grade glioma, and lung adenocarcinoma. Immune regulation and TME were both regulated by HTGPCRs. Using single-cell analysis, we found that the gene set of HTGPCRs correlated with many cancer-related functional states in retinoblastoma. Moreover, drug sensitivity and HTR4 were significantly correlated. Furthermore, we validated results in breast cancer and found knockdown of HTR1D inhibited breast cancer cell growth and metastasis. Conclusion: As prognostic indicators, HTGPCRs hold considerable promise and offer insights into the therapeutic targets for malignancy. Full article

The highly aggressive and invasive glioblastoma (GBM) tumour is the most malignant lesion among adult-type diffuse gliomas, representing the most common primary brain tumour in the neuro-oncology practice of adults. With a poor overall prognosis and strong resistance to treatment, this nervous system tumour requires new innovative treatment. GBM is a polymorphic tumour consisting of an array of stromal cells and various malignant cells contributing to tumour initiation, progression, and treatment response. Cannabinoids possess anti-cancer potencies against glioma cell lines and in animal models. To improve existing treatment, cannabinoids as functionalised ligands on nanocarriers were investigated as potential anti-cancer agents. The GBM tumour microenvironment is a multifaceted system consisting of resident or recruited immune cells, extracellular matrix components, tissue-resident cells, and soluble factors. The immune microenvironment accounts for a substantial volume of GBM tumours. The barriers to the treatment of glioblastoma with cannabinoids, such as crossing the blood–brain barrier and psychoactive and off-target side effects, can be alleviated with the use of nanocarrier drug delivery systems and functionalised ligands for improved specificity and targeting of pharmacological receptors and anti-cancer signalling pathways. This review has shown the presence of endocannabinoid receptors in the tumour microenvironment, which can be used as a potential unique target for specific drug delivery. Existing cannabinoid agents, studied previously, show anti-cancer potencies via signalling pathways associated with the hallmarks of cancer. The results of the review can be used to provide guidance in the design of future drug therapy for glioblastoma tumours. Full article

Glioblastoma is a deadly disease, with a mean overall survival of less than 2 years from diagnosis. Recurrence after gross total surgical resection and adjuvant chemo-radiotherapy almost invariably occurs within the so-called peritumoral brain zone (PBZ). The aim of this narrative review is to summarize the most relevant findings about the biological characteristics of the PBZ currently available in the medical literature. The PBZ presents several peculiar biological characteristics. The cellular landscape of this area is different from that of healthy brain tissue and is characterized by a mixture of cell types, including tumor cells (seen in about 30% of cases), angiogenesis-related endothelial cells, reactive astrocytes, glioma-associated microglia/macrophages (GAMs) with anti-inflammatory polarization, tumor-infiltrating lymphocytes (TILs) with an “exhausted” phenotype, and glioma-associated stromal cells (GASCs). From a genomic and transcriptomic point of view, compared with the tumor core and healthy brain tissue, the PBZ presents a “half-way” pattern with upregulation of genes related to angiogenesis, the extracellular matrix, and cellular senescence and with stemness features and downregulation in tumor suppressor genes. This review illustrates that the PBZ is a transition zone with a pre-malignant microenvironment that constitutes the base for GBM progression/recurrence. Understanding of the PBZ could be relevant to developing more effective treatments to prevent GBM development and recurrence. Full article

Dysregulation of clusterin (CLU) has been demonstrated in many cancers and has been proposed as a regulator of carcinogenesis. However, the roles of CLU in gliomas remain unclear. The expression of CLU was assessed using TIMER2.0, GEPIA2, and R package 4.2.1 software, leveraging data from TCGA and/or GTEx databases. Survival analysis and Cox regression were employed to investigate the prognostic significance of CLU. Immune infiltration was evaluated utilizing TIMER2.0, ESTIMATE, and CIBERSORT. The findings reveal the dysregulated expression of CLU in many cancers, with a marked increase observed in glioblastoma and lower-grade glioma (LGG). High CLU expression indicated worse survival outcomes and was an independent risk factor for the prognosis in LGG patients. CLU was involved in immune status as evidenced by its strong correlations with immune and stromal scores and the infiltration levels of multiple immune cells. Additionally, CLU was co-expressed with multiple immune-related genes, and high CLU expression was associated with the activation of immune-related pathways, such as binding to the antigen/immunoglobulin receptor and aiding the cytokine and cytokine receptor interaction. In conclusion, CLU appears to play crucial roles in tumor immunity within gliomas, highlighting its potential as a biomarker or target in glioma immunotherapy. Full article

Exosomes constitute small extracellular vesicles that contain lipids, proteins, nucleic acids, and glycoconjugates from the secreted cells and are capable of transmitting signals between cells and coordinating cellular communication. By this means, they are ultimately involved in physiology and disease, including development, homeostasis, and immune system regulation, as well as contributing to tumor progression and neurodegenerative diseases pathology. Recent studies have shown that gliomas secrete a panel of exosomes which have been associated with cell invasion and migration, tumor immune tolerance, potential for malignant transformation, neovascularization, and resistance to treatment. Exosomes have therefore emerged as intercellular communicators, which mediate the tumor–microenvironment interactions and exosome-regulated glioma cell stemness and angiogenesis. They may induce tumor proliferation and malignancy in normal cells by carrying pro-migratory modulators from cancer cells as well as many different molecular cancer modifiers, such as oncogenic transcripts, miRNAs, mutant oncoproteins, etc., which promote the communication of cancer cells with the surrounding stromal cells and provide valuable information on the molecular profile of the existing tumor. Moreover, engineered exosomes can provide an alternative system for drug delivery and enable efficient treatment. In the present review, we discuss the latest findings regarding the role of exosomes in glioma pathogenesis, their utility in non-invasive diagnosis, and potential applications to treatment. Full article