Gliomas are primary brain tumors known for their resistance to radiotherapy and frequent recurrence. This might result from the high heterogeneity and transcriptional plasticity of gliomas. Heat shock proteins are associated with unfavorable tumor outcomes and protect tumors from the effects of radiotherapy. However, their influence on brain tumors is not fully understood. Initial analyses of glioma patients from the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases who had undergone radiotherapy identified HSP90B1 as a crucial gene affecting patient prognosis. Subsequent investigations revealed that HSP90B1 enhanced the proliferation, migration, and invasion of glioma cells. It was also found to protect glioma cells from radiotherapy-induced apoptosis. Co-immunoprecipitation (CO-IP) found that HSP90B1 directly interacted with RhoC and protected it from degradation via the ubiquitin-proteasome pathway. Rescue experiments indicated that HSP90B1 might facilitate glioma migration, invasion, and radiotherapy resistance by modulating RhoC expression. A mouse model further demonstrated that gliomas expressing high levels of HSP90B1 exhibited decreased sensitivity to radiotherapy. Overall, our research revealed that HSP90B1 significantly impacts the prognosis of glioma patients treated with radiotherapy. Additionally, HSP90B1 might enhance glioma metastasis and resistance to radiotherapy by regulating RhoC expression. This regulatory effect was achieved by the directly binding of HSP90B1 to RhoC, thereby preventing its degradation through the ubiquitin-proteasome pathway.

Intracranial metastases (IM) are far more common than primary malignant brain tumors, yet remain understudied, representing an important unmet clinical need. Although patients with IM have historically been excluded from clinical trials, thus limiting assessment of intracranial treatment efficacy, their inclusion is increasing; however, patients with suspected leptomeningeal metastatic disease (LMD) remain commonly excluded, likely due to poorer prognosis and anticipated limited treatment response. Despite established treatment response criteria for confirmed LMD, there is limited guidance on how LMD should be diagnosed or excluded in broader IM trials, creating substantial risk for variability and misclassification. This article addresses the gap by proposing MRI-based criteria for classifying IM appearances with respect to LMD suspicion, focusing on the exclusion of LMD, illustrated with real patient examples. IM-related MRI findings are categorized into three groups: (a) imaging consistent with LMD, not requiring cerebrospinal spinal fluid confirmation; (b) equivocal findings warranting further evaluation with cerebrospinal fluid analysis or spinal MRI; and (c) imaging with low suspicion for LMD. Common pitfalls, mimics, and recommended next steps for equivocal findings are discussed. Keywords: Intracranial Metastasis, Leptomeningeal Metastatic Disease, MRI © RSNA, 2026.

Glioblastoma (GBM) is the most aggressive primary brain tumor with currently no treatment with long-term efficacy. Systematic relapses and therapeutic resistance are partly associated with the presence of glioblastoma stem cells (GSC) within the tumor. Existing options to overcome GSC protection are limited. Characterizing GSC resistance mechanisms appears crucial to identify efficient targeted inhibitors. A GSC model obtained by dedifferentiation of GBM cell lines (dGSC) was previously validated for GSC characteristics. In this study, viability of dGSC after treatment with diversified cytotoxic drugs was compared to parental cell lines. GSC phenotype acquisition is associated with a greatly decreased sensitivity to most cytotoxic drugs. Proteins expression, cell cycle and iron dosage analyses demonstrated that dGSC resistance acquisition is accompanied by decreased proliferation, STAT3 and Akt activation, increased iron storage and protection against oxidative stress. BMI1 and EZH2 epigenetic regulators are associated with resistance in GBM and were expressed in both dGSC and GBM cells. Akt activation in dGSC could redirect EZH2 toward histone methylation independent functions, through S21 phosphorylation. BMI1 and EZH2 inhibition decreased viability in both GBM cells and dGSC. Notably, EZH2 inhibition through GSK343 decreased proliferation and Akt activation, without impacting EZH2-associated epigenetic modification (H3K27me3), but with the induction of a ferroptosis signature. GSK343 effects on viability, proliferation and ferroptosis were confirmed in two lines of patient-derived GSC. GSK343 overcame resistant dGSC protection to trigger cell death by a mechanism involving oxidative stress. To conclude, GSK343-mediated EZH2 inhibition efficiently eliminated resistant GSC through ferroptosis, in a H3K27me3-independent manner.

Single-cell transcriptomics reveal PRRC1 as a malignant cell enriched driver of DNA repair and therapy resistance in glioblastoma.

Mitochondrial reverse electron transport regulates glioma stemness through Sirt3-HIF1α-SOX2 signaling.

The brain imaging feature-related gene NRP2 drives the malignant progression of glioblastoma through the FAK pathway: a Mendelian randomization study.

Multiform glioblastoma (GBM) is the most aggressive primary brain tumor, associated with high heterogeneity, treatment resistance, and poor survival. Temozolomide (TMZ), although the main chemotherapeutic agent used, shows limited efficacy due to low solubility, chemical instability, and acquired resistance. In this context, nanostructured systems can enhance their antitumor efficacy. This study aimed to develop and characterize chitosan-functionalized nanostructured lipid carriers loaded with Temozolomide (NLCTQ), as well as to assess their biological activity in human glioblastoma cells (U87-MG). Lipid nanoparticles functionalized with chitosan were prepared by hot emulsification and sonication. Physicochemical characterization included DLS, zeta potential, FTIR, and HPLC for drug quantification and encapsulation efficiency. Biological activity was evaluated in U87-MG cells using the cell viability assay MTT and trypan blue, the comet assay, the spheroid model, fluorescence cell death, and the CBMN assay. The formulation presented a homogeneous nanometric size and positive zeta potential, although with moderate encapsulation efficiency (39%). Biological assays demonstrated that NLCTQ significantly reduced cell viability, overcoming the U87-MG cell line's resistance to TMZ by achieving cytotoxicity at doses up to 20 times lower than free TMZ. Additionally, NLCTQ promoted the formation of biomarkers of chromosomal instability, such as micronuclei, bridges, and nuclear buds, which may explain the observed cytotoxic effects. Together, the results indicate that TMZ nanoencapsulation in NLCTQ enhances its antitumor efficacy, representing a promising strategy to overcome the limitations of conventional chemotherapy in glioblastoma treatment.

Modeling glioblastoma relapse in vitro: a critical journey from 2D models to organ-on-chip alternatives

Intracranial sarcomas can arise secondarily from primary brain tumors, including gliomas and meningiomas, either spontaneously or following radiotherapy. The current WHO classification recognizes sarcomatous transformation in several tumor entities; however, sarcomas arising from meningiomas remain poorly characterized and are regarded as a possible histological manifestation within the spectrum of anaplastic meningiomas. We analyzed nine matched meningioma-sarcoma pairs using integrated histopathological assessment and molecular profiling, including DNA methylation analysis, next-generation sequencing, copy number profiling, and proteomics. Although recurrent sarcomatous tumors were clonally related to their meningioma precursors-sharing identical NF2 alterations and overlapping chromosomal aberrations-they demonstrated pronounced divergence at the histological, immunophenotypic, and epigenetic levels. Importantly, sarcomatous transformation occurred in four cases without prior radiotherapy. Sarcomatous recurrences exhibited loss of meningothelial markers and acquired expression of cytokeratin and myogenic markers. DNA methylation profiling revealed a shift away from canonical meningioma signatures toward profiles resembling non-meningothelial mesenchymal tumors. Proteomic analysis showed consistent upregulation of SOX2 in sarcomatous tumors compared with their primary counterparts, suggesting acquisition of stem-like features during lineage divergence. Clinically, these tumors were associated with aggressive growth, early recurrence, and extracranial metastases, resembling malignant sarcomas more closely than anaplastic meningiomas. In addition, analysis of an institutional cohort of NF2-mutant intracranial tumors (n = 316) suggests that sarcomas with inactivating NF2 mutations may originate from meningiomas even in the absence of a clinically recognized precursor. Together, these findings suggest that sarcomatous transformation represents a rare evolutionary endpoint in NF2-mutant meningiomas, marked by clonal continuity but pronounced biological divergence. These results highlight limitations of morphology-based classification and emphasize the value of integrated molecular diagnostics in distinguishing these tumors from conventional high-grade meningiomas. Given their sarcoma-like behavior despite a meningioma ancestry, these tumors may not be adequately captured by current meningioma grading schemes.

Gliomas are the most common type of primary brain tumors. Their management options and outcomes depend significantly on the underlying molecular-marker profile. Traditionally, molecular markers are determined through pathological testing on a tissue specimen acquired through biopsy. Several Magnetic Resonance Imaging (MRI) based Deep Learning (DL) methods offer a promising, non-invasive approach to predict these markers. However, they often require high-quality, well-annotated datasets. To support this need, we present a well-curated brain tumor dataset developed at The University of Texas Southwestern (UTSW) Medical Center. This dataset includes multi-contrast-MRI, demographics, molecular-markers, and multi-label tumor segmentations for 625 patients treated at UTSW between 2006 and 2023. Each patient record contains four MRI contrasts: pre-contrast-T1w, post-contrast-T1w, T2w, and T2-weighted fluid-attenuated inversion recovery (T2w-FLAIR) images. The dataset also provides comprehensive genetic information, including IDH mutation-status, 1p19q co-deletion, MGMT promoter methylation, tumor-type, and tumor-grade. This dataset offers a valuable resource for exploring the relationship between MRI characteristics and tumor genetics. It also serves as a robust benchmark for developing and validating DL models for various downstream tasks.

Brain metastasis in breast cancer patients represents a terminal disease stage, with median survival typically measured in months. Tumors that colonize the brain must adapt to its unique microenvironment, such as high acetate levels. Primary brain tumor cells enhance acetate conversion to acetyl-CoA through phosphorylation of acetyl-CoA synthetase 2 (ACSS2) by cyclin-dependent kinase 5 (CDK5), a process regulated by the nutrient sensor O-GlcNAc transferase (OGT). In this study, we showed that brain-metastatic breast cancer cells exhibited elevated O-GlcNAc, OGT, and phosphorylated ACSS2 (Ser267) compared to their parental counterparts. Both OGT and CDK5 were essential for in vivo tumor growth in the brain, and ACSS2 and a phospho-mimetic S267D mutant drove progression of brain metastatic breast cancer. Mechanistically, ACSS2 supported tumor cell survival by suppressing ferroptosis through E2F1-dependent transcription of the anti-ferroptotic protein SLC7A11. Treatment with brain-penetrant ACSS2 inhibitor AD-5584 induced ferroptosis and significantly suppressed breast cancer brain metastatic growth ex vivo and in vivo. Together, these findings identify ACSS2 as a key metabolic regulator of brain-metastatic breast cancer survival and a promising target for ferroptosis-inducing therapies.

Lay Summary Accurately differentiating actual tumor progression from treatment-related changes, such as pseudoprogression or radiation-induced injury, remains one of the most critical diagnostic challenges in neuro-oncology for both primary and secondary brain tumors. Conventional MRI often lacks specificity because it primarily reflects blood-brain barrier disruption rather than viable tumor tissue. Consequently, advanced techniques like perfusion-weighted MRI and amino acid PET have gained significant attention. While perfusion-weighted MRI provides essential insights into blood flow and is widely available, accumulating evidence suggests that amino acid PET can be more reliable in identifying treatment-related changes. Since both modalities offer complementary information, there is an ongoing debate regarding their relative roles and the optimal way to integrate them into clinical practice. Combining these tools aims to provide more reliable diagnoses, ultimately preventing unnecessary interventions and ensuring that true tumor growth is detected as early as possible.

Primary brain tumors are life-threatening diseases. Glioblastoma is the most aggressive type with a poor prognosis. Medulloblastoma is the most common pediatric brain tumor. While surgical treatments often result in recurrences owing to the complex nature of the tumor microenvironment, conventional treatments lower the quality of life of patients by causing serious side effects. Therefore, cutting-edge therapies are required to alleviate patients' burden. Phytochemicals such as curcumin, quercetin, berberine, and resveratrol have been shown as potential therapeutic agents by demonstrating anticancer activity, including the inhibition of cell migration and proliferation, and the induction of apoptosis. This review summarizes the pharmacokinetic and cellular effects of phytochemicals that can be utilized in the treatment of medulloblastoma and glioblastoma by targeting cellular pathways associated with the progression of these diseases. Additionally, the synergistic relationships of these phytochemicals with traditional drugs and the emerging studies that utilize nanotechnology to ensure effective delivery of phytochemicals are covered in this review.

Primary and metastatic brain tumors exhibit resistance to immunotherapies that demonstrate efficacy in peripheral cancer settings. While many immunotherapies aim to enhance CD8+ T cell infiltration and functionality in established tumors, identification of neoantigens support emerging immunopreventative tactics against brain cancer. Functionally potent tissue-resident memory CD8+ T cells (TRM) can be generated in the brain following peripheral infection or vaccination. However, the ability of brain TRM to prevent intracranial malignancy remains unknown. Here, mice were seeded with tumor-specific or bystander brain TRM via peripheral infection prior to depletion of circulating memory T cells (TCIRCM) and subsequent brain tumor challenge. Tumor-specific brain TRM durably protected mice against intracranial malignancy even in the absence TCIRCM. These brain TRM persisted in tumor-surviving mice and protected against a second antigen-matched challenge. Importantly, a translationally-relevant mRNA-lipid nanoparticle (LNP) vaccine phenocopied peripheral infection-induced outcomes, generating functional brain TRM that controlled tumor growth. Altogether, this work points to the utility of brain TRM in cancer immunoprevention, supporting the development of antitumor mRNA-LNP vaccines to bolster brain immunity.

Glioblastoma (GBM) is the most lethal primary brain tumor with limited treatment options. Perfluorooctanoic acid (PFOA), a ubiquitous "forever chemical" classified as a group 1 carcinogen by the IARC, can cross the blood-brain barrier and accumulate in neural tissue. This study aimed to determine the causal relationship between genetically predicted higher circulating PFOA levels and GBM risk, elucidate underlying molecular mechanisms, and identify potential therapeutic targets using an integrated multi-omics framework. Two-sample Mendelian randomization (MR) analysis was conducted using 23 single-nucleotide polymorphisms as instrumental variables. The outcome data were derived from the FinnGen consortium (endpoint C3_GBM, defined by ICD-O-3 morphology code 9440/3 with topography C71), with statistical analysis performed using SAIGE with saddlepoint approximation to address case-control imbalance. Network toxicology was applied to identify shared targets between PFOA and GBM, followed by protein-protein interaction network analysis and hub gene screening. The significance of gene set overlap was assessed using hypergeometric testing. Gene Ontology and KEGG enrichment analyses were performed on the full set of 86 overlapping genes to clarify biological pathways. Molecular docking assessed potential binding interactions between PFOA and hub proteins, and drug-target interaction analysis was conducted using the DGIdb database. MR analysis demonstrated a significant causal association between genetically predicted higher circulating PFOA levels and increased GBM risk (IVW OR = 2.64, 95% CI 1.13-6.20, p = 0.017), with no evidence of pleiotropy or heterogeneity. Network toxicology identified 86 overlapping targets (hypergeometric test p = 2.31 × 10⁻1⁸, OR = 3.12) and 9 hub genes (IL1B, MYC, BCL2, ALB, EGFR, ESR1, IL6, TNF, CASP3). Enrichment analyses of all 86 overlapping genes highlighted the AGE-RAGE signaling pathway, response to xenobiotic stimulus, chemical carcinogenesis-receptor activation, and positive regulation of glial cell proliferation. Molecular docking predicted potential PFOA binding to all hub proteins (binding energy < - 6.0kcal/mol), with strongest affinities for MYC and TNF. Cisplatin emerged as the top drug repositioning candidate. This study provides the first genetic evidence supporting genetically predicted higher circulating PFOA levels as a causal risk factor for glioblastoma, potentially mediated by AGE-RAGE-driven neuroinflammation and oncogenic pathway activation, highlighting both environmental risk implications and therapeutic opportunities.

PGK1/PHGDH axis drives radioresistance in glioblastoma stem cells.

To identify specific, sensitive, and non-invasive circulating protein biomarkers that could facilitate the diagnosis of brain metastasis (BrM) and improve risk prediction for BrM among patients with non-small cell lung cancer (NSCLC). We performed data-independent acquisition mass spectrometry (DIA-MS)-based proteomic profiling of 14 tissue specimens obtained from 7 patients, together with 89 serum samples from NSCLC and NSCLC-BrM cohorts, to identify candidate biomarkers associated with BrM. A total of 12,808 proteins were identified in the tissue proteome and 6041 proteins in the serum proteome, representing an extensive proteomic analysis of lung cancer with BrM reported to date. Using integrated analyses, we identified a four-protein classifier that served as biomarkers for predicting the risk of NSCLC metastasis to the brain. Notably, PSMA4, LAP3, and LZIC were consistently downregulated in both the sera and tissues of patients with NSCLC-BrM compared with those with NSCLC without BrM. These biomarkers were subsequently validated by ELISA in an additional cohort, demonstrating high concordance with the PRM results. Immunohistochemical analyses further supported the utility of these proteins in distinguishing BrM from primary brain tumors. The integrated analysis of tissue and serum proteomics across the cohorts supports the potential value of proteomics-guided, biomarker-assisted diagnosis and risk prediction in BrM and may help enable more accurate stratification and more targeted treatment strategies.

Pleomorphic Xanthoastrocytomas (PXAs) are rare pediatric brain tumors accounting for approximately 1% of primary brain neoplasms in children and young adults. Despite recent imaging and molecular advances, gaps remain in our understanding of their diverse imaging characteristics and clinical outcomes. This study provides a large international, multi-institutional analysis of pediatric PXAs focusing on neuroimaging and clinical outcomes. We conducted a retrospective international multi-center study including 63 pediatric patients with histologically confirmed PXAs. Neuroimaging data were reviewed, and molecular analyses were recorded with emphasis on BRAF V600E mutations and CDKN2A/B deletions. Treatment modalities and clinical outcomes, including progression-free and overall survival, were analyzed using statistical survival models. 73.3% of tumors were CNS WHO grade 2 and 26.7% were CNS WHO grade 3. The median age at diagnosis was 10.7 (IQR 6.9) years. CNS WHO grade 3 tumors were significantly larger at diagnosis, with a median volume of 87,920 mm³ compared with 14,925 mm³ for grade 2 tumors (p = 0.03). BRAF V600E mutations were identified in 78% of cases and CDKN2A/B deletions in 93.5%. On MRI, PXAs typically appeared well-defined, with cortical and leptomeningeal contact (86.0% and 56.4%, respectively), frequent cysts (59.6%), and intermediate diffusivity (mean ADC 1005 × 10-6 mm2/s). CT imaging showed most tumors were isointense to gray matter (52.0%), with hydrocephalus more common in grade 3 tumors (71.4% vs. 26.3%, p = 0.07). Gross total resection was achieved in 73.7% of cases and was associated with improved progression-free survival, independent of age at diagnosis and tumor grade (HR = 0.39; 95% CI, 0.16-0.96; p = 0.041). Larger tumor volume correlated with poorer survival outcomes (HR = 3.47; 95% CI, 0.83-14.4; p = 0.087), also independent of tumor grade and age at diagnosis. Tumor recurrence occurred in 44.8% of patients at three years. The estimated three-year overall survival rate was 94.7%. Pediatric PXAs exhibit distinct neuroimaging and molecular features correlating with prognosis. Integrated evaluation of radiological and clinical features is critical to improve risk stratification and guide personalized therapeutic strategies in this rare tumor population.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor with a poor prognosis. Magnetic resonance imaging (MRI) is widely used for the clinical diagnosis and prognostic evaluation of GBM. This study aimed to investigate the relationship between MRI semantic features and overall survival, and to explore the underlying biological mechanisms by transcriptomic analysis. In this study, we reviewed the MRI images of 171 patients with GBM from The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases and evaluated twelve MRI semantic features. Cox regression model and Kaplan-Meier survival curve were used to assess the prognostic value of the imaging features. Additionally, we investigated the relationship between imaging features and gene expression using differential gene expression and enrichment analysis in the cohort of 68 tumor samples with RNA-seq data. 171patients with GBM were included in the imaging-prognostic cohort (median age was 60.0 years and 59.6% were male). In the multivariate analyses, age (HR: 1.04, 95% CI: 1.03-1.06, P < 0.001), ependymal extension (HR:1.88, 95% CI:1.32-2.69, P < 0.001), contrast-enhancing tumor (CET) crossing midline (HR:2.38, 95% CI:1.16-4.91, P = 0.018) were significantly associated with shorter overall survival (OS). Gene set enrichment analysis (GSEA) showed that these features were significantly associated with pathways involved in inflammatory responses and tumor invasiveness, such as TNF-α signaling via NF-κB and epithelial-to-mesenchymal transition. Our study demonstrated that MRI semantic features, including ependymal extension and CET crossing the midline, can serve as prognostic indicators for patients with GBM. Additionally, several selected MRI features were found to be associated with specific biological pathways, potentially informing treatment decisions based on these distinctive semantic characteristics of GBM.

Glioblastoma is the most aggressive primary brain tumor with no cure, largely because of tumor heterogeneity and immunosuppressive tumor microenvironment. Chimeric antigen receptor (CAR)-T cell therapy is highly effective in blood cancers but exhibits limited efficacy in glioblastoma due to heterogeneous tumor antigen expression, antigen loss and poor persistence of tumor-targeting immune cells in glioblastoma. Here we show a multimodal immunotherapy strategy that integrates engineered immune cells with oncolytic viruses to overcome these barriers. We have developed bispecific CAR-T and CAR-NK cells in combination with oncolytic virus that delivers two tumor antigens to glioblastoma cells for effective CAR targeting. Moreover, oncolytic virus armed with membrane-bound interleukin-15 and interleukin-21 enhances immune cell expansion/persistence and cytotoxic activity. This combined approach improves anti-tumor efficacy in vitro and in vivo by limiting immune escape and enhancing anti-tumor immunity. Together, these findings establish a promising platform for multimodal immunotherapy targeting glioblastoma and other solid tumors.