Homozygous deletion of the methylthioadenosine phosphorylase (MTAP) gene occurs in 10-15% of all human cancers and up to 50% of high-grade malignant gliomas, representing one of the largest opportunities for precision oncology. Loss of MTAP leads to the accumulation of 5'-methylthioadenosine (MTA), which sensitizes tumor cells to inhibition of protein arginine methyltransferase 5 (PRMT5). Herein we describe the discovery of TNG456, a potent and highly selective MTA-cooperative PRMT5 inhibitor that is brain penetrant in preclinical species and currently in Phase I/II clinical studies for the treatment of advanced or metastatic solid tumors with MTAP loss, with a focus on glioblastoma.

Pediatric brain tumors, including high-grade gliomas (HHG), medulloblastomas (MB), and ependymomas (EPN), are a leading cause of death in children. They are often immunologically "cold" with low tumor mutational burden (TMB) and very few tumor-infiltrating lymphocytes (TILs), which may limit the role of immune checkpoint inhibitors (ICI). We performed a PRISMA‑guided systematic review of PubMed/MEDLINE, Embase, and Scopus from inception to September 17, 2025, for English-language studies of patients ≤ 21 years with primary CNS tumors treated with PD‑1/PD‑L1 or CTLA‑4 inhibitors. Eligible reports included prospective trials, retrospective series, and observational/case reports with extractable data on efficacy and/or toxicity. Of 479 records identified, 386 unique citations were screened, 127 underwent full‑text review, and 40 met inclusion criteria for qualitative synthesis. Prospective and institutional studies in biomarker-unselected diffuse midline glioma, high-grade glioma, medulloblastoma, and ependymoma showed low objective response rates (generally ≤ 6%), short median progression-free survival (1-3 months), and overall survival similar to historical controls, despite acceptable safety (grade ≥ 3 treatment-related adverse events ~ 15-25% with anti-PD-1 ± anti-CTLA-4). In contrast, across germline MMR-deficient and broader RRD/hypermutant cohorts, PD-1 blockade produced clinically meaningful and sometimes durable responses, including complete remissions in malignant glioma and approximate 2-year overall survival near 50%, often with delayed responses and pseudoprogression. Histology-specific profiling highlighted marked variation in immune contexture: pediatric gliomas segregate into immune "hot," "altered," and "cold" subtypes; medulloblastoma is largely PD-L1-low with prominent B7-H3 and myeloid programs; checkpoint expression is also observed in germ cell and selected sellar tumors. Evidence quality is limited by small, heterogeneous, predominantly non-comparative designs. ICIs show manageable safety but limited efficacy in unselected pediatric CNS tumors. Durable benefit is most evident in RRD/hypermutant biology and possibly PD-L1-high niches (e.g., some low-grade gliomas and CNS-GCT). Future trials should be biomarker-driven and pair ICIs with priming combinations (e.g., radiation, epigenetic modulators, metronomic chemotherapy) to convert "cold" tumors into responders.

The optimal order of treatment with programmed cell death protein 1 (PD-1) inhibitor immunotherapy and stereotactic radiosurgery (SRS) in malignant gliomas remains unclear. This study examined whether the timing of PD-1 inhibitor administration relative to SRS affects patient neurological outcomes and survival in a multi-institutional propensity score-matched cohort. A retrospective analysis was conducted using the TriNetX Research Network database (2005-2022), identifying adults with malignant gliomas who received SRS and at least one PD-1 inhibitor. Patients were stratified into two cohorts based on whether PD-1 inhibition occurred 8 weeks before SRS (pre-SRS) versus after SRS (post-SRS). Propensity score matching (1:1) was performed for demographics, comorbidities, and relevant medications. Clinical outcomes, including mortality, cognitive impairments, cranial nerve deficits, seizures, hemorrhagic complications, and functional impairments, were assessed over a 3-year follow-up period. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated, and Kaplan-Meier (KM) survival analyses were used to compare cumulative incidence rates. Before matching, the pre-SRS (n = 429) versus post-SRS (n = 381) cohorts differed significantly in sex (female, unknown), ethnicity (Hispanic/Latino, unknown), race (Asian, American Indian, other), overweight/obesity, type 2 diabetes mellitus, lipidemia, anticoagulant use, durvalumab use, and atezolizumab use (all p < 0.05). After propensity score matching (n = 233 per group), PD-1 inhibition pre- versus post-SRS showed no significant differences in baseline characteristics except for age (mean 63.50 [SD 11.84] years vs 63.36 [SD 10.82] years, p = 0.012) and tremelimumab use (n = 0 [0%] vs n = ≤ 10 [≤ 4.29%], p = 0.001). In propensity score-matched patients, PD-1 inhibitor use before SRS was associated with significantly higher odds of cognitive impairments (OR 1.75, 95% CI 1.04-2.98, p = 0.034), cranial nerve deficits (OR 2.00, 95% CI 1.11-3.69, p = 0.021), and mortality (OR 1.53, 95% CI 1.06-2.20, p = 0.023), while other outcomes including behavioral/mood changes (OR 0.91, p = 0.726), gait/coordination disorders (OR 1.28, p = 0.421), hemorrhagic complications (OR 0.97, p = 0.930), motor deficits (OR 0.86, p = 0.590), seizures/epilepsy (OR 0.99, p = 0.971), and sensory disturbances (OR 0.91, p = 0.737) showed no significant differences. KM analyses confirmed elevated risks of cognitive impairment (p = 0.0076), cranial nerve deficits (p = 0.0104), and mortality (p = 0.0109) in the pre-SRS group. Pre-SRS PD-1 inhibitor use was associated with more neurological deficits and lower survival, highlighting the need for prospective studies on optimal SRS immunotherapy timing in malignant gliomas.

This study presents a crucial advancement in controlling the safety and function of neurotropic viruses. We engineered a dual-purpose ZIKV, ZIKV-miR124T, which is regulated by the brain-specific microRNA, miR-124. This design forces the virus to strongly self-suppress in healthy neural tissue, solving a major safety concern for ZIKV-based therapies. ZIKV-miR124T is shown to be a potent oncolytic agent against malignant glioma while also serving as a highly effective, safe live-attenuated vaccine against ZIKV infection, reducing vertical transmission to the fetus. Our work provides a strong demonstration of utilizing microRNA regulation to achieve precise viral tropism and attenuation, offering a valuable, generalizable strategy for the development of safer and more effective viral therapies and vaccines against neurotropic pathogens.

Gliomas exhibit substantial intratumoral heterogeneity, which limits prognostic precision and therapeutic efficacy. Selenoproteins are key regulators of redox homeostasis, but their role in glioma progression remains insufficiently defined. This study aimed to characterize glioma cells with high selenoprotein activity and to determine their biological and clinical significance. We performed integrated multi-omic analyses combining bulk transcriptomic, single-cell transcriptomic, and spatial transcriptomic data to identify and characterize glioma cell states associated with elevated selenoprotein expression. Functional validation was conducted using SELENOS knockdown assays to evaluate effects on glioma proliferation, invasion, tumor growth, macrophage recruitment, CSF1 expression, and macrophage polarization. We identified a malignant glioma cell state, termed SehighMali, characterized by elevated selenoprotein expression and distinct metabolic and immunological features. SehighMali cells showed enhanced oxidative phosphorylation, MYC-associated transcription, and DNA repair activity, and preferentially engaged in immunosuppressive crosstalk with myeloid cells through the CSF1-CSF1R axis. Spatial analyses demonstrated enrichment of SehighMali cells in tumor cores and close colocalization with immunosuppressive myeloid populations. Across bulk cohorts, higher SehighMali abundance was associated with aggressive molecular features, poor clinical outcomes, and a predicted temozolomide-resistant phenotype. SELENOS knockdown suppressed glioma proliferation, invasion, and tumor growth, reduced macrophage recruitment, decreased CSF1 expression, and promoted macrophage polarization toward a pro-inflammatory phenotype. These findings define a selenoprotein-driven malignant glioma state associated with immune evasion and therapeutic vulnerability. They further identify SELENOS as a potential therapeutic target and provide insight into how selenoprotein-related programs contribute to glioma progression.

Activin receptor-likekinase 2 (ACVR1/ALK2) regulates bone morphogeneticprotein signaling, and ALK2 modulation has been identified as a promisingtherapeutic strategy for conditions including fibrodysplasia ossificansprogressiva (FOP), diffuse intrinsic pontine glioma (DIPG), and glioblastoma.Herein, we report on the development of first-in-class ALK2 degraders,including M4K3233 (13), a potent and selectivecompound that was utilized as a chemical tool to study the mechanismof ALK2 degradation. Subsequent optimization of this compound resultedin M4K3250 (20), a compound with improvedALK2 degradation potency. The compounds described have utility forstudying the role of ALK2 in human disease and possess translationalpotential in drug discovery.

Intra-arterial chemotherapy (IAC) is used to increase the delivery of chemotherapy agents for intracranial tumours, but its clinical value across diseases remains uncertain. We evaluated the clinical outcomes of IAC across intracranial tumours. We systematically searched PubMed, Embase, Scopus and Web of Science until April 2025 (PROSPERO CRD420251056066). Eligible clinical studies evaluated IAC as primary, neoadjuvant, concurrent or salvage therapy and reported quantitative outcomes. For time-to-event outcomes we preferentially extracted and reconstructed hazard ratios (HRs). Random-effects meta-analysis was undertaken where comparable data permitted; small-study effects were explored with funnel plots and Egger's test. Of 1302 records, 155 studies were included in the qualitative synthesis (retinoblastoma, malignant gliomas, head-and-neck squamous-cell carcinoma (HNSCC), and other tumours). IAC achieved high globe-salvage with low systemic toxicity in retinoblastoma. However, in gliomas and skull-based HNSCC, radiographic responses occurred in subsets. A meta-analysis of four studies in glioma showed no significant difference in survival (pooled HR 1.07, 95 % CI 0.95-1.21; prediction interval 0.70-1.65), with evidence of funnel-plot asymmetry (Egger's p = 0.001). Between-study heterogeneity was extreme, and most studies were at serious or critical risk of bias. Toxicities were regimen-dependent, and catheter-related neurovascular events were uncommon. Current evidence supports the role of IAC in ocular retinoblastoma. For gliomas, HNSCC and other skull-base tumors, IAC remains investigational where survival benefit over systemic therapy is unproven. Generally, the pharmacologic advantages of IA delivery alone have not translated into a consistent survival benefit outside retinoblastoma.

Quantification of the Kiel 67 (Ki-67) labeling index (LI) is critical for assessing proliferation and prognosis in tumors but manual scoring remains a common practice. We present an automated framework for Ki-67 scoring in whole slide images (WSIs) developed for research settings using an Apache Groovy code script for QuPath and complemented by a Python postprocessing script that provides cell density maps and summary tables. Tissue segmentation is performed by pixel classifiers and cell segmentation is conducted using StarDist, a deep learning model, followed by adaptive thresholding to classify Ki-67 positive and negative nuclei. The pipeline was applied to a cohort of 632 pediatric brain tumor cases with 734 Ki-67 WSIs from the Children's Brain Tumor Network. Medulloblastomas showed the highest Ki-67 LI (median: 19.84), followed by atypical teratoid rhabdoid tumors (median: 19.36), brainstem glioma-diffuse intrinsic pontine gliomas (median: 11.50), high-grade gliomas (grades 3, 4) (median: 9.50), and ependymomas (median: 5.88). Lower indices were found in meningiomas (median: 1.84) and the lowest were seen in low-grade gliomas (grades 1, 2) (median: 0.85), dysembryoplastic neuroepithelial tumors (median: 0.63), and gangliogliomas (median: 0.50). The results demonstrate a significant correlation (P < .05) in Ki-67 LI across most of the tumor families/types aligning with neuro-oncology and neuropathology consensus.

Triple-targeted artificial extracellular vesicles for enhanced glioma therapy via synergistic chemomagnetic penetration of the blood-brain barrier.

Microglia accumulate in malignant gliomas and play a pivotal role in tumor progression. Using single‑cell RNA sequencing studies researchers have probed gene expression in the myeloid cells in experimental gliomas at relatively late stages of the tumor development. Therefore, the early changes in gene expression in microglia in response to glioma are not fully characterized. We have previously reported distinct profiles of gene expression in the rat primary microglia cultures treated for 6 hours with either rat C6 glioma‑conditioned medium (GCM) or lipopolysaccharide. In the current study, using RNA‑seq, we characterized the transcriptional response of rat primary microglia to GCM in vitro at different time‑points: 6 h, 24 h, and 48 h, as compared to the control treated for 6 h with its own medium. We observed that during the GCM treatment gene expression changes in a biphasic, swing‑like pattern. This includes the genes involved in innate immune response, which are mostly down‑regulated at 6 h by the GCM treatment, as compared to the time‑matched control, and subsequently up‑regulated at 48 h, as compared to the earlier time‑points of the GCM treatment. Conversely, the genes involved in the cell cycle are up‑regulated at 6 h and down‑regulated at 48 h, which coincides with the induction of Tgfb1. Notable exceptions to this biphasic pattern include key genes activating immune response, such as Tlr9 and Myd88, which are down‑regulated early and persistently, while genes inhibiting immune activation, such as Trem1, and genes involved in a metabolic switch, such as Pfkl, are persistently up‑regulated. Most notably, the up‑regulated genes include Ptgs1 (alias Cox1) and Tbxas1, which encode the enzymes catalyzing the synthesis of thromboxane A2, a known inducer of T cell suppression. Further studies are needed to test the functional consequences of their up‑regulation.

Advances in organoid and other three-dimensional culture systems, single-cell and spatial transcriptomics, multi-omics, and high-resolution imaging are reshaping our understanding of the cellular origins and evolutionary trajectories of glioblastoma. When integrated with modern data science approaches, these technologies enable the construction of increasingly detailed molecular biographies of normal neural stem and progenitor cells as well as malignant stem-like cellular states. Such molecular biographies illuminate how developmental programs, cellular plasticity, and microenvironmental cues are co-opted during gliomagenesis. At the same time, progress in machine learning, immunotherapy, and precision molecular targeting is beginning to translate these biological insights into therapeutic strategies that specifically disrupt glioblastoma stem-like states. Together, these converging approaches provide a conceptual and technological framework for improved tumor modeling, earlier detection, and increasingly personalized therapies for malignant gliomas.

Diffuse intrinsic pontine glioma (DIPG) is the pediatric tumor with the worst prognosis. BIOMEDE was a randomized phase 2 trial comparing the efficacy in terms of overall survival (OS) (primary endpoint) of epidermal growth factor receptor (EGFR) inhibitor erlotinib, mTOR inhibitor everolimus and multitargeted tyrosine kinase inhibitor dasatinib in combination with radiotherapy in patients with a biopsy-proven DIPG. Tumors were assessed centrally for immunohistochemical biomarkers (EGFR overexpression or PTEN loss) together with whole-exome and RNA sequencing. A cohort of 66 children with the same inclusion criteria and treated previously with temozolomide-based regimen was used to compare outcome. Treatment allocation was performed by randomization in 233 patients, designed so that a drug could not be allocated if the corresponding biomarker was absent: 36 received erlotinib, 102 received dasatinib and 95 received everolimus. The trial was ended for futility of the primary endpoint following the recommendations of the independent data monitoring committee: OS from biopsy was not different from the control cohort (median OS = 10.8 months (95% confidence interval (CI): 9.5-13.0)) in any of the three arms (median OS = 9.7 months (95% CI: 7.8-14.6) for erlotinib; 9.9 months (95% CI: 8.8-11.2) for dasatinib; and 11.9 months (95% CI: 10.7-14.2) for everolimus). Everolimus showed significantly less ocular, renal, skin and gastrointestinal side effects and treatment discontinuation for toxicity (secondary endpoint). TP53 mutations, frequently linked to multiple structural chromosomal aberrations, were the strongest predictor for poor survival in multivariate analysis (hazard ratio = 2.8 (95% CI: 1.9-4.2), P < 0.0001). Both mutations in and activation of the mTOR pathway were associated with a better response to everolimus. Four long-term survivors treated with an mTOR inhibitor were alive free of treatment over 6 years from diagnosis. With comprehensive tumor profiling, BIOMEDE validated prognostic biomarkers as well as informative theranostic biomarkers for future trials. ClinicalTrials.gov: NCT02233049 .

The prognosis of DIPG is still dismal. Despite transient clinical improvement after treatment, there is usually minimal or no radiologic regression and radiological complete response is very rare. Here, we report a child with DIPG who had radiological complete response and long-term survival treated with radiotherapy and adjuvant temozolomide. The initial MRI of a 9-year-old boy demonstrated large pontine mass causing expansion with the largest diameter of 35mm, partially encasing the basilar artery and indenting the anterior wall of the 4th ventricle suggestive of DIPG. He received radiotherapy concomitant temozolomide orally 75mg/m2/day during radiotherapy. Six weeks after radiotherapy, the MRI revealed significant reduction in the size of the pontine mass. Treatment was followed by oral temozolomide 200mg/m2/day × 5days every 28days for 12 cycles. After 12 courses of chemotherapy MRI demonstrated complete regression of the pontine mass with an area of sequelae hemorrhage. The patient was followed up with complete radiologic response and no evidence of disease for three and a half years after completion of treatment, after which he relapsed and despite further treatment died due to progressive disease 6 years after diagnosis. There are a few reports in the literature indicating radiological complete response in DIPG. Although some imaging features such as extrapontine extension and greater craniocaudal dimensions are unfavorable prognostic factors, there is no defined radiologic response characteristic for prognosis in the literature. More studies are needed to predict a model for assessing the radiological response and prognosis.

Prolonged survival in pediatric diffuse intrinsic pontine glioma following intensity-modulated radiation therapy: a case report

Malignant gliomas remain among the most challenging brain tumors to manage, with high recurrence rates and difficulty in distinguishing progression from treatment-related changes. While the peritumoral region offers valuable insights into tumor behavior, its quantitative MRI characteristics remain largely underexplored. This study investigated the diagnostic and prognostic value of multiparametric MRI biomarkers from noncontrast-enhancing peritumoral regions, particularly the surrounding nonenhancing FLAIR hyperintensity (SNFH). Thirty-eight patients with treated malignant gliomas underwent amide proton transfer-weighted (APTw) imaging, T1 and T2 mapping, and diffusion-weighted imaging. Histogram analysis of signal intensities from the enhancing tumor, immediate SNFH (≤ 10 mm), and distant SNFH regions was performed. Progression cases typically showed APTw hyperintensity in enhancing tumor cores and surrounding SNFH, while response cases showed minimal hyperintensity to isointensity in these regions. Repeated measures ANOVA revealed significant parameter variation across the tumor and SNFH regions, with APTw showing the largest dynamic range. Logistic regression models trained on histogram features from APTw and T1 maps achieved a maximum test area under the curve (AUC) of 0.79 in differentiating progression from response. In survival analysis, parameters including higher APTw skewness was associated with better overall survival (hazard ratio = 0.32; p = 0.006). These findings demonstrate that APTw and T1 imaging biomarkers from peritumoral edema regions reflect key features of tumor invasion and metabolic activity. Their combined application has potential to improve diagnostic accuracy and inform prognosis in posttreatment high-grade gliomas.

組織内PDT（interstitial photodynamic therapy: i-PDT）は腫瘍組織にレーザー光照射ファイバーを穿刺し，腫瘍組織内部よりPDTを行う手法である．今回，我々は悪性脳腫瘍細胞の皮下および脳内移植動物モデルを対象とし，細径プラスチックファイバーを腫瘍組織中心に穿刺，talaporfin sodiumを用いたi-PDTを行い，腫瘍組織の傷害性を検討した．結果として，いずれのモデルにおいてもPDTによる腫瘍組織傷害性が確認され，その病理像は腫瘍血管傷害性の凝固壊死と，TUNEL陽性を示すapoptosisの混在が主体であった．各照射条件を検討した結果，同一エネルギー密度の照射の場合，低パワー密度で長時間照射した方が，より強く，広範囲な腫瘍組織傷害性が得られることが判明した．これらの結果から，従来行ってきた脳腫瘍組織摘出後の摘出腔に対する表面照射法に加え，組織内照射法というオプションも脳腫瘍治療に役立つ可能性が示唆された．

Radio-dynamic Therapy with 5-Aminolevulinic Acid for Malignant Glioma: Alterations in the Expression of Immune- and Angiogenesis-Related Factors

Glioblastoma (GBM) is a frequent malignant glioma among astrocytic tumors. Traditional pathological diagnostic criteria inadequately capture the underlying biological heterogeneity, highlighting the need for novel biomarkers to improve the diagnostic and prognostic accuracy of GBM. Based on the GBM-related data from The Cancer Genome Atlas (TCGA), Replication Stress-related Genes (RSGs) were collected. The RSG feature scores were calculated by ssGSEA and combined with WGCNA to screen target module genes. Enrichment analysis of the modular signature genes was conducted using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Prognostic genes were screened by univariate Cox and multivariate Cox regression analyses to establish a prognostic model for GBM. The Tumor Microenvironment (TME) was assessed using MCPcounter and TIMER methods. Immunotherapeutic responses and drug sensitivity responses were evaluated using the TIDE method. Finally, the role of PDCL3 in GBM was explored via immunohistochemistry, qRT-PCR, wound-healing, and transwell assays. WGCNA identified RSG-associated module genes enriched in DNA replication, DNA-dependent ATPase activity, and other pathways. Four characterized genes (PDCL3, STEAP2, NXPH4, MPST) were selected to establish a Riskscore model for GBM. The risk score of the model was significantly related to the infiltration of myeloid dendritic cells, endothelial cells, and fibroblasts. The Riskscore was significantly positively correlated with the TIDE score, indicating higher immune escape potential in the high-risk group. The high-risk group was sensitive to Vinorelbine and Crizotinib. Through in vitro experiments, it was observed that knocking down PDCL3 noticeably inhibited the viability, migration, and invasion capacities of U87 cells. This study validated the correlation between Oncogene-induced Replication Stress (ORS) characteristics and the prognosis of GBM, and screened RSGs to develop a Riskscore for GBM applying multiple types of regression analyses. We constructed and verified a four-gene ORS-based prognosis model for GBM, linking replication stress to immune evasion and drug sensitivity for the first time. Experimental validation confirmed the pro-tumorigenic role of PDCL3, offering potential biomarkers and therapeutic targets.

We investigated changes in O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status in 21 patients with malignant gliomas who underwent two or more surgeries. Tumor specimens from multiple surgeries were analyzed using methylation-specific polymerase chain reaction (MS-PCR) and immunohistochemistry (IHC) for MGMT. Patients were divided into two groups: Group A (13 recurrent cases with therapeutic intervention) and Group B (8 cases of recurrence without therapeutic intervention or planned two-stage surgeries). MGMT methylation status was compared between initial and recurrent specimens, and in Group A, progression-free survival (PFS) and overall survival (OS) were analyzed according to MGMT methylation status at both initial and recurrent surgeries. By MS-PCR, changes in Group A were as follows: methylated to unmethylated in 23.1%, unchanged in 61.5%, and unmethylated to methylated in 15.4%. In Group B, changes were methylated to unmethylated in 12.5%, unchanged in 87.5%, and no cases of unmethylated to methylated. The difference in proportions between the groups was not significant (p = 0.13). By IHC, changes in Group A were methylated to unmethylated in 7.7%, unchanged in 53.8%, and unmethylated to methylated in 38.5%. In Group B, changes were methylated to unmethylated in 12.5%, unchanged in 87.5%, and no cases of unmethylated to methylated. The difference in proportions between the groups was significant (p = 0.034). Excluding one grade 3 case, in the 12 patients of Group A, median OS from treatment initiation differed by MGMT status assessed by immunohistochemistry in recurrent specimens (26.5 vs. 90.0 months, p = 0.043). These findings suggest that immunohistochemical assessment may capture spatial heterogeneity of MGMT status that is not readily detected by MS-PCR, and that therapeutic intervention may be associated with dynamic changes in MGMT methylation status. Furthermore, MGMT status assessed by IHC in recurrent specimens was associated with overall survival, indicating its potential prognostic relevance.

Diffuse midline glioma, H3 K27-altered, formerly known as diffuse intrinsic pontine glioma, (DIPG/DMG) is the most aggressive form of pediatric brain malignancy, with <10% 2-year overall survival after standard of care. The limited success of traditional immune checkpoint inhibitors in pediatric high-grade gliomas, including DMG, has highlighted the urgent need to re-examine the tumor's intrinsic and microenvironmental barriers to immunotherapy. Advances in molecular and spatial profiling have revealed the profound intratumoral heterogeneity, lineage plasticity, and complex immunosuppressive tumor microenvironment characteristic of DMG, which are shaped by diverse myeloid populations, neuronal integration, and spatially distinct tumor niches. These insights are informing the development of non-traditional immunotherapeutic approaches, including alternative checkpoint blockade, chimeric antigen receptor T cells, and viro-immunotherapy strategies, which aim to overcome DMG's unique immune escape mechanisms. We also outline key translational challenges and future directions necessary to accelerate progress, including the refinement of preclinical models, optimization of central nervous system (CNS)-specific immunotherapy delivery, and the integration of patient-derived data into streamlined, collaborative clinical trial platforms.