Abstract Glioblastoma (GBM) remains a formidable challenge in neuro-oncology, with immune checkpoint blockade (ICB) only showing efficacy in some patients, while the mechanisms governing therapeutic responsiveness are poorly defined. Although MAPK/ERK signaling correlates with survival following ICB, its causal role and mechanisms underlying tumor immunogenicity remain unclear. Here, we perform in vivo kinome-wide CRISPR/Cas9 screens in murine gliomas where we identify RAF-MEK-ERK axis as the strongest modulators of glioma susceptibility to anti-programmed cell death protein 1 (anti-PD-1) therapy and CD8 + T cell recognition. Experimentally-induced ERK phosphorylation (p-ERK) enhances survival after anti-PD-1 and anti-CTLA-4 therapy, leading to durable antitumor immunity upon rechallenge. Additionally, glioma cell p-ERK promotes increased interferon responses and T cell infiltration. Notably, BRAF/MEK inhibition disrupts interferon programs and tumor-microglia interactions in BRAF V600E ex vivo in human GBM/brain slice cultures. Our findings elucidate that tumor-intrinsic MAPK/ERK promotes immunotherapy response, interferon responses, T cell tumor infiltration, and GBM cell-microglia interactions.

Background Chordomas are locally aggressive notochordal tumors with no systemic therapy options. As an ultra-rare cancer type, our understanding of its immune landscape is limited. While tumor-associated macrophages (TAMs) and T cells are critical components of the immune landscape, their functional states and interactions remain poorly understood.Methods We conducted an integrative analysis of 35 chordoma samples and six paired tumor-PBMC samples using single-cell RNA sequencing (scRNA-seq), T-cell receptor (TCR) profiling, and multiplex immunofluorescence. Immune cell phenotypes, spatial distribution, TCR motif diversity, and functional states were assessed using unbiased co-expression network analysis and predictive modeling.Results Chordomas exhibited remarkable immune cell heterogeneity, ranging from highly infiltrated to immune-desert tumors. Tumor-associated macrophages dominated the tumor microenvironment (TME) and were enriched for antigen-processing pathways. T-cell receptor profiling revealed clonal overlap between tumor-infiltrating and peripheral T cells, suggesting systemic anti-tumor responses. Exhausted CD8+ T cells exhibited restricted clonality and tumor-specific amino acid motifs. Weighted gene co-expression network analysis (WGCNA) identified gene modules associated with immune activation and suppression, underscoring the dual roles of immune cells in the TME. Spatial analysis revealed fibrous septa as immune interaction hubs, where immune cell clustering was significantly higher than in tumor regions.Conclusions This study advances understanding of the chordoma immune landscape by integrating spatial, transcriptomic, and TCR data. The findings highlight systemic and local immune dynamics, reveal tumor-specific TCR motifs, and identify potential therapeutic targets. These insights provide a foundation for developing personalized immunotherapies to overcome immune suppression and enhance anti-tumor immunity in chordomas.

Survival is poor for patients with recurrent glioblastoma. We prospectively investigated the use of tremelimumab (CTLA-4 inhibitor) and durvalumab (PD-L1 inhibitor) given pre- and post-surgery to assess clinical activity and safety, and to understand the intratumoral immunologic changes. This report focuses on clinical outcomes. Recurrent glioblastoma patients were randomized to either: Arm 1, tremelimumab (75 mg every 4 weeks IV); Arm 2, durvalumab (750 mg every 2 weeks); or Arm 3, combination (tremelimumab 75 mg every 4 weeks for 7 doses then every 12 weeks along with durvalumab 750 mg every 2 weeks). Eligible patients received treatment 14 days prior to surgery, then underwent clinically indicated resection, followed by adjuvant treatment starting within 28 days after surgery. Thirty-one patients were evaluable. Median OS and PFS for the entire cohort was 8.9 months (95

Ganglioglioma and gangliocytoma are rare, predominantly low-grade neuroepithelial tumors that commonly present with epilepsy in children and young adults. Advances in molecular profiling have improved understanding of their pathogenesis, highlighting key roles for the mitogen-activated protein kinase/ERK signaling pathway. Diagnosis relies on a combination of clinical, radiologic, and histopathologic features, with complete surgical resection offering the best clinical outcomes. This review summarizes current knowledge on their epidemiology, etiology, clinical presentation, imaging characteristics, pathology, treatment strategies, and prognosis.

Meningiomas are common tumors of the central nervous system that are typically treated with surgery or radiation, but lack established systemic therapies. Activation of the stimulator of interferon genes pathway with an agonist such as 8803 can trigger anti-tumor immune responses. Using integrated molecular approaches, here we show that this pathway is targetable in both neoplastic and immune populations within the meningioma microenvironment. Meningioma tumor cells exhibit promoter hypomethylation and increased chromatin accessibility of the STING genomic locus, associated with robust expression of this gene. Treatment of diverse patient meningiomas ex vivo with 8803 induces direct tumor cytotoxicity through inflammatory cell death pathways, including induction of gasdermin D membrane pore formation. Release of necrotic tumor debris triggered by 8803 activates macrophages and upregulates matrix metalloproteinase production, facilitating degradation of extra-cellular collagen. Injection of preclinical meningiomas with 8803 induces survival benefits, including in an immunocompetent orthotopic setting, through remodeling of the tumor microenvironment, immune infiltration, and downregulation of tumor-mediated immune suppression, thereby nominating 8803 for treatment consideration in meningiomas.

Von Economo neurons (VENs) are unique spindle-shaped neurons that primarily reside in the anterior cingulate (ACC) and fronto-insular (FI) cortices. They are more numerous in species with affiliative behaviors and may support social-emotional functions. VENs are reduced in the ACC and FI of individuals with behavioral variant frontotemporal dementia (bvFTD), marked by personality changes and socially inappropriate behavior. Neuropathologies underlying bvFTD include frontotemporal lobar degenerations (FTLD) with tauopathy (FTLD-tau) or TDP-43 (FTLD-TDP). This study examined VEN density across three FTLD-tau subtypes: the 4R tauopathies of corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), and the 3R tauopathy known as Pick's disease (PiD). Twenty-six right-handed bvFTD-FTLD-tau cases were identified from the Northwestern University Alzheimer's Disease Research Center brain bank (PiD n = 9; CBD n = 11; PSP n = 6). Paraffin sections were cresyl violet-stained to visualize VENs in the ACC and analyzed using unbiased stereology. Wilcoxon rank-sum tests showed significantly lower VEN density in PiD than CBD (P < 0.05). No significant differences were found between PiD and PSP or CBD and PSP. Across isoforms, VEN density was over fourfold higher in 4R than 3R cases (P < 0.01). Overall, stereology indicates VENs are more vulnerable to 3R PiD than 4R CBD, both causes of bvFTD. The clinical implications of this differential vulnerability warrant further study.

Purpose: Is maximal safe resection performed by a single surgeon associated with better overall survival and preserved functional outcomes in elderly patients with GBM compared to biopsy alone in a single-institution with homogenous clinical protocols? Methods: We conducted a single-surgeon, single-center retrospective cohort study of patients aged ≥ 70 years treated between 2016 and 2024, including a subgroup of octogenarians, to compare survival following resection versus biopsy for lobar GBM. Results: Among 82 patients, 65 (79.3%) underwent resection and 17 (20.7%) biopsy. Median survival was significantly longer after resection than biopsy (8.8 vs 2.7 months). On multivariate Cox analysis adjusting for radiation, temozolomide, MGMT status, and ASA score, resection remained associated with improved survival (HR = 0.34, 95% CI = 0.19–0.63, p < 0.001). The survival benefit persisted in both MGMT-methylated and unmethylated tumors but was observed only among patients receiving adjuvant therapy. In octogenarians, resection was independently associated with improved survival (HR = 0.28, 95% CI = 0.10–0.81, p = 0.018), with greatest benefit in MGMT-methylated tumors and those treated with temozolomide. Functional outcomes were preserved following resection, with 63.6%, 69.2%, and 70.8% maintaining ECOG < 2 at 3, 6, and 12 months, respectively, including octogenarians. Nine patients (11%) survived beyond two years; all achieved gross total resection, had MGMT-methylated tumors, and completed full adjuvant therapy. Conclusions: By minimizing inter-surgeon variability and applying uniform adjuvant protocols, these findings support consideration of maximal safe resection in carefully selected elderly GBM patients when combined with multimodal treatment.

BACKGROUND:Primary central nervous system immunodeficiency/dysregulation-associated lymphoproliferative disorders (PCNS-IDD-LPDs) are a rare and heterogeneous group of lymphoid lesions that arise within the CNS of immune compromised patients. Among PCNS-IDD-LPDs, monomorphic IDD-LPDs are relatively well studied; however, data regarding PCNS polymorphic IDD-LPDs is very limited. It remains unclear whether polymorphic PCNS IDD-LPDs follow a similarly indolent clinical course as observed in their systemic polymorphic counterparts, or whether the unique immune microenvironment of the CNS imparts a more aggressive disease biology. METHODS:In this study, we compared the clinical, pathologic, and survival profile of PCNS polymorphic IDD-LPDs (N = 15) with extra-CNS polymorphic IDD-LPDs (N = 21) as well as PCNS monomorphic IDD-LPDs (N = 12). RESULTS:Compared to extra-CNS polymorphic IDD-LPDs, patients with PCNS polymorphic IDD-LPDs showed a significantly stronger association with kidney transplants, longer latency, worse performance status, more frequent monoclonal populations and necrosis, and a greater need for aggressive chemoimmunotherapy in addition to reduction in immunosuppression and/or rituximab. The overall survival (OS) of PCNS polymorphic IDD-LPDs was significantly inferior to that of extra CNS polymorphic IDD-LPDs (median survival: 7.1 years vs. not reached; log-rank p = 0.023) and not significantly different from PCNS monomorphic IDD-LPDs (median survival: 7.1 vs. 3.6 years; log-rank p = 0.852). CONCLUSION:We conclude that PCNS polymorphic IDD-LPDs have a uniquely aggressive clinicopathologic and prognostic profile compared to their systemic counterparts and are comparable to their monomorphic PCNS counterparts. CNS localization supersedes the histological subtype as the primary determinant of disease biology in IDD-LPDs, likely ascribed to the immune sanctuary status of the CNS.

MGMT promoter methylation is an important predictor of response to chemotherapy in adult-type diffuse gliomas. Currently, MGMT promoter methylation assessment requires formalin-fixed, paraffin-embedded (FFPE) tissue. We developed a droplet digital PCR (ddPCR) MGMT assay performed on bisulfite converted DNA utilizing primers targeting CpG positions with known clinical utility, which we validated against DNA methylation array (98.7% concordance). Smear preparations are routine for intraoperative neurosurgical consultation; thus, we sought to validate ddPCR using smear preparations. Thirty-six smears were collected during intraoperative consultation. For the first 28 samples, DNA from smears was extracted and bisulfite converted, and MGMT promoter methylation was quantified by ddPCR. These results were compared to DNA methylation array. For the final 8 samples, slides were H&E-stained and cover slipped for cellularity assessment prior to DNA extraction and directly compared with corresponding FFPE specimens. The smear ddPCR method showed concordance in 81.6% of cases, with a sensitivity of 85%, specificity of 100%, positive predictive value of 100% and negative predictive value of 81.3%. This novel approach will reduce turnaround time (approximately 2 days) over conventional MGMT analysis with FFPE and could provide clinically pertinent information for treatment planning and clinical trial enrollment options prior to discharge of the patient.

Meningiomas are the most common primary brain tumors and, despite their benign reputation, often behave aggressively. Meningiomas are morphologically heterogeneous, yet the full significance of their histologic diversity is unclear. This is in large part because many features are not readily quantifiable by traditional observer-based light microscopy. Molecular testing improves prognostic stratification, but is not universally accessible. We therefore sought to determine whether an artificial intelligence (AI)-trained program could predict specific genomic and epigenomic patterns in meningiomas, and whether it could extract more prognostic information out of standard hematoxylin and eosin (H&E) histopathology than the current WHO classification. To do this, we developed Morphologic Set Enrichment (MSE), an interpretable computational pathology framework that quantifies statistical enrichment of morphologic patterns, cells, and tissue architecture from H&E whole-slide images. The MSE meningioma histology program was able to accurately predict DNA methylation subtypes and concurrent chromosome 1p/22q losses, in the process identifying specific morphologic patterns associated with key genomic and epigenomic alterations. It also added prognostic value independent of standard clinical and pathological variables. These results demonstrate that AI-based quantitative morphologic profiling can capture clinically and biologically relevant information that redefines risk stratification for meningiomas, incorporating histological information not included in existing grading schemes. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the US National Institutes of Health National Cancer Institute P50CA221747, U54CA302435, National Institute of Neurological Disorders and Stroke U24NS133949, R01NS117104, R01NS118039, and National Library of Medicine award R01LM013523. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Review Board of Northwestern University gave ethical approval for this work, including approval under protocol STU00213676 and approval from the Northwestern University Nervous System Tumor Bank under protocol STU00095863. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. Processed data is available online at https://drive.google.com/drive/folders/1R0OBOIWIrbp\_5tiURGnkwRmc\_al5kBWZ?usp=share_link

ABSTRACT Tumor-associated myeloid cells (TAMCs) dominate the glioblastoma (GBM) microenvironment and suppress anti-tumor immunity. Here, we identify cholesterol efflux via ABCA1 as a targetable metabolic checkpoint controlling TAMC immunosuppression in GBM. Reprogramming TAMC cholesterol metabolism using TAMC-targeting lipid nanoparticle encapsulating ABCA1 siRNA (ABCA1 LNP) converts TAMCs into potent antigen-presenting cells with enhanced pro-inflammatory activity and antigen-presenting capacity, thereby inducing T cell activation, expansion, and tumor infiltration. Mechanistically, ABCA1 blockade induces cholesterol accumulation in TAMC membranes, promoting lipid raft formation and enhancing MHC-I-mediated antigen presentation. In multiple preclinical GBM models, ABCA1 LNP treatment dramatically induces T cell priming, extends animal survival, and overcomes GBM resistance to radiotherapy and immune checkpoint therapy. This efficacy was well-maintained in stem-like and recurrent GBM models, GBM patient specimens, and a renal cell carcinoma model. Altogether, our work identifies cholesterol efflux as a targetable metabolic vulnerability in TAMCs to overcome therapy resistance in myeloid-rich, immunologically “cold” tumors.

Astrocytes play essential roles in various functions including ionic homeostasis, energy metabolism, neurotransmission, and regulation of the blood-brain barrier. Researchers have reported that hyperphosphorylated tau in astrocytes can be identified in postmortem, particularly in individuals over the age of 60 years. Astrocytic p-tau has also been reported in association with chronic traumatic encephalopathy neuropathologic change (CTE-NC). This study investigates possible association between subpial aging-related tau astrogliopathy (ARTAG) and a history of playing high school American-style football. Postmortem brain tissue samples were obtained from 176 men (median age at death = 65 years; range = 50-96) from the Lieber Institute for Brain Development. There were 128 with no known history of participating in contact or collision sports and 48 (27.3%) who participated in football. Subpial ARTAG was identified in 23 cases (13.1%). Those who participated in football had a higher percentage with subpial ARTAG than those who did not participate in football (20.8% vs 10.2%), although this difference was not statistically significant (P =.061). The 2 groups did not differ in the percentages who had subpial ARTAG in a sulcal depth (10.4% of former football players and 7.8% of controls). More research is needed to understand possible associations between subpial ARTAG, aging, and CTE-NC.

Is surgical resection associated with better overall survival and preserved functional outcomes in elderly patients with GBM compared to biopsy alone in a single-institution with homogeneous clinical protocols? We conducted a single-surgeon, single-center retrospective cohort study of patients aged ≥ 70 years treated between 2016 and 2024 to compare survival following resection versus biopsy for lobar GBM. Among 82 patients, 65 (79.3

Corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) comprise the majority of 4-repeat (4R) tauopathy cases of frontotemporal lobar degeneration (FTLD-tau). Both pathologic entities can underlie clinical syndromes such as primary progressive aphasia (PPA), characterized by an isolated, progressive impairment of language and left-predominant atrophy, and behavioral variant frontotemporal dementia (bvFTD), marked by progressive personality changes and more symmetric frontotemporal atrophy. In this study, we investigated the neocortical and hippocampal distributions of neuronal and glial tau inclusions in CBD and PSP to establish clinicopathologic concordance between tau pathology and the aphasic versus behavioral phenotype. Twenty-eight right-handed cases with autopsy-confirmed CBD (n=14) or PSP (n=14) were identified from the Northwestern University Alzheimer's Disease Research Center brain bank (PPA, n=16; bvFTD, n=12). Paraffin-embedded sections were immunohistochemically stained with AT8 to visualize tau pathology, and modified unbiased stereological analysis was performed in up to eight regions, including the middle frontal gyrus (MFG), superior temporal gyrus (STG), inferior parietal lobule (IPL), anterior temporal lobe (ATL), dentate gyrus (DG), CA1 of the hippocampus, and primary visual cortex (V1). In PPA, pathology was significantly left-lateralized, with the ATL showing the highest overall tau burden, while bvFTD cases showed more symmetric or rightward distributions with peak pathology in the MFG. Across both syndromes, CBD cases exhibited greater neuronal tau pathology, and PSP cases exhibited greater glial tau pathology, with this double-dissociation reaching significance across neocortex. Hippocampal regions, particularly CA1, showed higher neuronal tau burden than neocortical regions regardless of clinical phenotype, and DG tau burden was significantly greater in CBD than PSP (p<0.01). Inclusion-to-neuron analyses revealed disproportionately higher tau burden in the DG compared to neocortex, especially in CBD (p<0.001). These findings reveal syndrome- and pathology- specific patterns of selective cellular and regional vulnerability in 4R-tauopathies and support clinicopathologic concordance in PPA and bvFTD.