Neuro-oncology最新文献

Background: Mechanisms driving aggressive meningiomas remain poorly understood. Given the pivotal role of the immune microenvironment in tumor progression, we developed a comprehensive atlas of the meningioma microenvironment, with a view towards identifying modifiable opportunities.

Methods: The immune microenvironment of 2,727 meningiomas was profiled using orthogonal methodologies, including 24 with mass cytometry, 24 single-cell RNAseq, 1,437 bulk RNAseq, 1,125 DNA methylation, 117 multiplex immunofluorescence, as well as that of 5 paired peripheral blood samples and 10 human meninges. Patient-derived organotypic tumor spheroids (PDOTS) were established to assess the effect of STING stimulation combined with anti-PD-1 treatment.

Results: We revealed a rich immune infiltration in meningioma, among the highest across 34 human cancer types (n = 12,188). Macrophages predominated in meningioma microenvironment, in contrast to the lymphoid dominance of peripheral blood, with meninges exhibiting an intermediate immune profile between meningiomas and peripheral blood. Cellular states and phenotypes of both immune and tumor cells shifted during tumor progression, with aggressive meningiomas possessing earlier-stage, immunosuppressive immune cells and proliferative tumor cells. Using ex vivo meningioma PDOTS, we demonstrated inducible responses to STING activation, marked by elevated cytokine release, which were synergistic when combined with PD-1 blockade.

Conclusions: These findings offer an extensive resource on the cellular heterogeneity of the meningioma microenvironment and provide a framework for rational therapeutic modeling and strategy development.

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 CNS-specific immunotherapy delivery, and the integration of patient-derived data into streamlined, collaborative clinical trial platforms.

Background: Metastasis remains a critical determinant of survival in neuroblastoma (NB), yet the role of transcriptional dysregulation, particularly super-enhancer (SE)-mediated transcriptional control in this process has not been elucidated. The aim of this study is to identify the SE-driven transcription factors involved in the metastasis of NB and potential targeted drugs.

Methods: The metastatic SE-driven Transcription Factor 4 (TCF4) was screened and identified by integrating bioinformatic analyses of H3K27ac ChIP-seq and scRNA-seq. The effect of TCF4 on NB cell metastasis was evaluated through in vivo and in vitro functional experiments. The molecular mechanism of TCF4 was investigated by the study of targeted CUT&Tag and transcriptome sequencing.

Results: TCF4 is associated with poor prognosis in patients and significantly promotes the metastasis ability of NB cells both in vivo and in vitro. Mechanistically, TCF4 transcriptionally activates SPTLC1, a pivotal enzyme in sphingolipid biosynthesis, to promote ganglioside GM3 synthesis. GM3 orchestrates membrane architecture remodeling, thereby modulating ITGB1 membrane localization and activation, which subsequently potentiates FAK signaling. Notably, we demonstrate that the HDAC6 inhibitor ACY-1215 suppressed NB malignancy by destabilizing TCF4 protein.

Conclusions: Our findings indicate that SE-driven TCF4 can orchestrate metastatic transcriptional networks to maintain NB malignancy and propose ACY-1215 as a translational therapeutic candidate for clinical intervention.

Background: DNA methylation profiling can be used to robustly predict postsurgical outcomes and response to radiotherapy (RT) for meningioma patients. To allow for seamless integration of these complementary models into clinical practice, a practical framework is needed.

Methods: We leveraged a cohort of nearly 2000 surgically-treated meningiomas with DNA methylation profiling and clinical outcomes data. Existing methylation-based prediction models were dichotomized to yield four risk groups: low and high recurrent risk, each with RT sensitive and resistant subgroups. Risk groups were correlated with progression-free survival in the context of existing biomarkers including extent of resection and WHO grade.

Results: We first demonstrated that all risk groups benefit from gross total resection. All "high-risk, RT sensitive" tumors (n = 306, 15.7%) also benefited from adjuvant RT: after GTR, median PFS increased from 4.68 (4.13-9.48) years to not reached (P = .003); after subtotal resection (STR), from 2.12 (1.59-3.02) to 4.09 (3.41-not reached) years (P = .004). "Low-risk, RT sensitive cases" (n = 1207, 61.8%) also benefited from RT after STR (median PFS 7.39 (6.66-12.8) vs. 16.53 (10.35-not reached) years, P = .03), suggesting that RT be considered in these patients. Neither "low-risk RT resistant" (n = 84, 4.3%) nor "high-risk RT resistant" (n = 356, 18.2%) cases benefited from RT, and the latter group was associated with universally poor outcomes.

Conclusions: We identify methylation-defined risk groups of meningioma for which additional benefit is gained from adjuvant RT, leading to a clinical decision-making framework for straightforward integration of molecular models into clinical practice.

Background: In vivo stable isotope tracing is useful for natively surveying glioma metabolism but can be difficult to implement. Stable isotope tracing is tractable using in vitro glioma models, but most models lack nutrient conditions and cell populations relevant to human gliomas. This limits our ability to study glioma metabolism in the presence of an intact tumor microenvironment (TME) and immune-metabolic crosstalk.

Methods: We optimized an in vitro stable isotope tracing approach for human glioma explants and glioma stem-like cell (GSC) lines that integrates human plasma-like medium (HPLM). We performed 15N2-glutamine tracing in GSC monocultures and human IDH-wildtype glioblastoma explants and developed an analytical framework to evaluate microenvironment-dependent metabolic features that distinguish them. We also conducted spatial transcriptomics to assess transcriptional correlates to metabolic activities.

Results: Human plasma-like medium culture preserved glioma explant viability and stemness while unmasking metabolic and immune programs suppressed by conventional culture conditions. Stable isotope tracing in HPLM revealed TME-dependent and TME-independent features of tumor metabolism. Tissue explants recapitulated tumor cell-intrinsic metabolic activities, such as synthesis of immunomodulatory purines. Unlike GSC monocultures, tissue explants captured tumor cell-extrinsic activities associated with stromal cell metabolism, as exemplified by astrocytic guanosine diphosphate mannose production in heterocellular explants. Finally, glioma explants displayed tumor subtype-specific metabolic reprogramming, including robust pyrimidine degradation in mesenchymal cells.

Conclusions: We present a tractable approach to assess glioma metabolism in vitro under physiologic nutrient levels and in the presence of an intact TME. This platform opens new avenues to interrogate glioma metabolism and its interplay with the immune microenvironment.

Background: With the growing adoption of stereotactic spine radiosurgery (SSRS), precise target delineation is essential. The International Spine Radiosurgery Consortium (ISRC) has proposed contouring guidelines covering both the tumor and adjacent structures, termed the elective field (EF). We designed this randomized trial comparing EF and involved field (IF)-contouring strategy to determine which yielded the lowest protocol-specified failure rate.

Methods: Patients with spinal metastases not requiring surgery were randomized 1:1 to receive 16 Gy in a single fraction via EF or IF SSRS. EF followed ISRC recommendations. IF comprised the gross tumor volume with an 8-mm isotropic intraosseous margin. We aimed to reject failure rates >10% at 6 months. Treatment failure was defined as grade ≥3 treatment-related toxicity or local progression.

Results: Between August 2019 and May 2024, 106 patients (164 segments) were analyzed. Fifty-two and 54 patients were randomized to EF and IF, respectively. The median follow-up was 41.6 months. At 6 months, the cumulative incidence of treatment failure (CIF) met the acceptability criteria (per-patient: EF 3.8% vs IF 7.5%, P = .42). By 12 months, EF group showed low CIF, both per-patient (3.8% vs 13.5%) and per-segment (2.6% vs 11.8%). CIF curves differed significantly between groups (Gray's test, per-patient: P = .03, per-segment: P = .02). In the IF group, two-thirds of the out-of-field or marginal recurrences could be enclosed by the EF contouring strategy.

Conclusions: EF and IF SSRS met the criteria for acceptable CIF at 6 months. With longer follow-up, EF demonstrated lower failure rates. ISRC contouring guidelines should be the standard practice.

Background: T cell-based immunotherapies have had limited success in glioma thus far. Here, we evaluate the literature on abundance, spatial distribution and phenotypical characteristics of T cells in the tumor micro-environment (TME) of IDH-mutant and IDH-wildtype glioma, with the aim to understand how these measures relate to immunotherapy resistance and to aid the development of immunotherapies for glioma.

Methods: Medline, Embase, Web of Science Core Collection, Google Scholar and the Cochrane Central Register of Controlled Trials were systematically searched up to May 6, 2025. Out of 4303 articles screened, 85 studies examining T cell immunity in human glioma were selected. We collected information about tumor subtype, grade, methods, T cell abundance, spatial distribution, phenotypes and prognostic significance.

Results: T cells are present in the glioma TME, but densities are heterogeneous and generally low, especially in IDH-mutant glioma. T cell abundance increases with higher WHO grade and upon recurrence. T cells cluster around blood vessels, especially in IDH-mutant glioma. Glioma-infiltrating T cells largely display a late-differentiated phenotype (CD45RA-CCR7-C62L-), expressing markers that signify sustained antigen activation and exhaustion (PD-1, CTLA-4, TIM-3, LAG-3, CD39, and TIGIT). This phenotype coincides with decreased anti-tumor cytotoxicity and is spatially enriched in the myeloid-rich, hypoxic tumor core. Prognostic significance remains controversial.

Conclusions: T cells in glioma are scarce, generally fully differentiated and functionally inert. Understanding and reinvigorating the deficient T cell response will be essential for successful immunotherapies. Future research should incorporate functional and spatial immune profiling to optimize and personalize immunotherapeutic strategies for glioma patients.

Background: Glioblastoma stem cells (GSCs), a stem-like tumorigenic subpopulation within glioblastoma (GBM), exhibit remarkable self-renewal capacity and therapeutic resistance. Zinc finger BED domain-containing protein 1 (ZBED1), a dual-function transcription factor and SUMO E3 ligase, has been implicated in oncogenic processes across malignancies, its functional role and regulatory mechanisms in GSCs remain enigmatic.

Methods: Multimodal approaches including, immunohistochemistry, immunoblotting, and immunofluorescence, were employed to evaluate ZBED1 expression patterns in GSCs and clinical GBM specimens. Functional characterization utilized in vitro models (proliferation assays, tumor-sphere formation assays, and limiting dilution analysis) complemented by in vivo orthotopic xenograft models. Mechanistic investigations integrated RNA sequencing, label-free proteomics, chromatin immunoprecipitation (ChIP), immunohistochemistry, and western blotting to delineate the EGFR/ZBED1 regulatory axis.

Results: We demonstrated that ZBED1 was significantly upregulated in GSCs and linked to unfavorable prognosis. Genetic ablation of ZBED1 significantly impaired GSC proliferation and self-renewal capacity while extending survival in xenograft models. Mechanistically, EGFR-mediated ZBED1 phosphorylation at tyrosine residues Y160/Y513 enhanced ZBED1-UBC9 interaction, promoting SUMOylation-dependent protein stabilization. Remarkably, ZBED1 reciprocally sustained EGFR expression through transcriptional repression of the E3 ubiquitin ligase PARK2, establishing a self-reinforcing EGFR/ZBED1/PARK2 signaling circuit critical for GSC maintenance.

Conclusions: Our findings elucidate a novel EGFR/ZBED1 positive feedback loop that drives GSC propagation and tumorigenesis, highlighting ZBED1 as an attractive candidate for therapeutic targeting in GBM.