bims-malgli 2026-06-21 papers

Issue of 2026–06–21
five papers selected by
Oltea Sampetrean, Keio University

Neuro Oncol. 2026 Jun 19. pii: noag134. [Epub ahead of print]

Tumor-associated epilepsy at diagnosis in glioblastoma patients reveals an inflammatory molecular signature and is associated with better overall survival.

Lilyana Dimova, Jenny Stritzelberger, Diyan Dimov, Jonas Ort, Hussam Aldin Hamou, Hans Clusmann, Oliver Schnell, Hajo Hamer, Florian Putz, Stefanie Corradini, Ludwig Singer, Arnd Dörfler, Franz Ricklefs, Richard Drexler, Matthias Simon, Dieter Henrik Heiland, Daniel Delev.

BACKGROUND: Glioblastoma (GB) is the most aggressive primary brain tumor in adults. Tumor-associated epilepsy at diagnosis (TAE) is common, yet its prognostic significance remains unclear.
METHODS: We analyzed a retrospective multicenter test cohort of 855 GB patients (Aachen, Hamburg, Bielefeld) and validated findings in a prospectively collected cohort of 344 patients (Erlangen). Survival was assessed using multivariable Cox regression, propensity score matching, and interaction modeling of TAE and extent of resection (EOR). Molecular profiling included methylation-based classification, epigenetic deconvolution, and spatial transcriptomics.
RESULTS: TAE was independently associated with improved survival (HR 0.81, 95% CI 0.69-0.99, P = .036, absolute survival advantage ∼4-5 months). This effect was validated in the independent cohort (C-index 0.68 (95% CI 0.62-0.74) and persisted in propensity-matched analyses (HR 0.74, 95% CI 0.56-0.96, P = .027). Interaction modeling revealed that gross total resection (GTR) improved survival in both groups but particularly in patients with TAE (EOR interaction HR 0.69, 95% CI 0.49-0.99, P = .041). In this subgroup, partial resection provided no significant advantage over biopsy, whereas patients without seizures benefited incrementally from both partial resection and GTR. Molecular analysis demonstrated enrichment of the RTK II subtype, differentiated cell states, and an inflammatory microenvironment in glioblastoma with TAE; tumors without seizures displayed neuronal and stem-like features. Functional validation using Electrogenomics showed that glioblastoma cortical slices with increased inflammatory score exhibited synchronization of action potentials characteristic for seizure-like epileptiform activity.
CONCLUSIONS: TAE at diagnosis is a favorable prognostic marker in GB, defining a biologically distinct subgroup. Seizure status modifies the prognostic effect of surgical resection, underscoring the importance of GTR particularly in patients presenting with TAE.

Keywords: Glioblastoma; methylation; overall survival; transcriptomics; tumor-associated epilepsy

DOI: https://doi.org/10.1093/neuonc/noag134

Oncogene. 2026 Jun 17.

Enhancing glioma immunotherapy by disrupting RBP-J-mediated NNMT signaling in tumor microenvironment.

Dan Zhang, Ning Guan, Xu Feng, Yanyun Wang, Lin Zhang, Jiabao Liu, Shoudan Zhang.

Glioma is a highly aggressive central nervous system malignancy characterized by profound immune evasion, the underlying mechanisms of which remain incompletely defined. This study investigated how the transcription factor RBP-J drives immune suppression through activation of NNMT in cancer-associated fibroblasts (CAFs). By integrating single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST), we identified a CAF-specific NNMT-high subpopulation enriched at the tumor margin and closely associated with M2 macrophages. Bioinformatic analyses using Seurat and Monocle3 delineated a stromal-immune regulatory network and highlighted RBP-J as a potential upstream regulator of NNMT. Mechanistic experiments demonstrated that RBP-J directly binds to the NNMT promoter and activates its transcription, leading to intracellular SAM depletion, reduced H3K27me3 levels, and epigenetic upregulation of SAA3. Elevated SAA3 promoted M2 macrophage recruitment and polarization, resulting in CD8+ T cell exhaustion and immune suppression. In vivo experiments using an orthotopic glioma model confirmed that NNMT-high CAFs accelerated tumor growth, increased M2 macrophage infiltration, and diminished CD8+ T cell activity. Importantly, combined treatment with an NNMT inhibitor and αPD-1 partially reversed the immunosuppressive microenvironment and significantly enhanced therapeutic efficacy. Collectively, this study identifies the RBP-J/NNMT/SAA3 axis as a critical stromal-driven mechanism of immune evasion in glioma and provides a rationale for targeting metabolic-epigenetic pathways to improve immunotherapy outcomes. Schematic Diagram Illustrating the Molecular Mechanism by Which RBP-J Promotes Immune Evasion in Glioma via Activation of NNMT in CAFs, Leading to H3K27 Demethylation-Mediated Upregulation of SAA3 and Subsequent Reprogramming of M2 Macrophages.

DOI: https://doi.org/10.1038/s41388-026-03844-3

Neuro Oncol. 2026 Jun 15. pii: noag139. [Epub ahead of print]

Multi-sampling allows intra-tumoral heterogeneity querying and vulnerability profiling in glioblastoma.

Diogo Moniz Garcia, Wan-Hsin Lin, Daniel P Wickland, Erik Jessen, Erik H Middlebrooks, Lauren E Haydu, Mieu Brooks, Ryan W Feathers, Lindsey Kinsella, Chris Sereduk, Steven S Rosenfeld, Nhan L Tran, Kaisorn L Chaichana, Panos Z Anastasiadis, Alfredo Quinones-Hinojosa.

BACKGROUND: Glioblastoma (GBM) remains a devastating cancer with limited treatment options, largely due to its heterogeneity. While supramaximal resection has recently provided survival benefits, therapeutic profiling of different tumor compartments, particularly its infiltrative edge remains largely unexplored.
METHODS: Here, we leveraged magnetic resonance imaging (MRI)-guided multi-sampling, collecting 2 cores and 2 margins per case, to query GBM heterogeneity. Whole-exome and RNA-seq with drug testing in two patient-derived 3D models were used to reveal similarities and differences in genomic and transcriptomic makeups, cellular compositions, and drug responses across cores and margins. Bioinformatics interrogations further identified response biomarkers.
RESULTS: Mutation analysis showed that oncogenes exhibited a higher degree of spatial heterogeneity than tumor suppressor genes, regardless of MRI status. While the mesenchymal transcriptional subtype with extracellular matrix remodeling, stress response, and immune programs were preferentially enriched in enhancing cores, proneural tumors with neurological processes favored non-enhancing margins. Using a 15-drug GBM-targeted panel, ERK (ulixertinib) and PI3K pathway (paxalisib, CC-115) inhibitors showed preferential efficacy in enhancing cores and non-enhancing margins, respectively. The anti-apoptosis, pan-Bcl2 agent navitoclax and the epigenetic drug trotabresib represented the most effective, tumor-wide monotherapies. Importantly, drug combinations generally outperformed single agents across all regions.
CONCLUSIONS: This work demonstrates the regional heterogeneity of therapeutic vulnerabilities in GBM ex vivo, showing various drugs with tumor-wide or MRI-enhancement informed activity. These findings offer preclinical bases of numerous monotherapies and drug combinations for future clinical trial design.

Keywords: 3D patient-derived models; Glioblastoma; IDH-wildtype; MRI enhancing status; drug testing; molecular and therapeutic heterogeneity

DOI: https://doi.org/10.1093/neuonc/noag139

Nat Commun. 2026 Jun 17.

IDH1-R132H enhances oncolytic HSV-1 therapy by facilitating viral entry and immune activation in glioma.

Eleni Panagioti, Hunter J Kelley, Alexander L Ling, Leinal Sejour, Shikha Saini, William F Goins, Daniel Roberts, Sotiris Sotiriou, J Bryan Iorgulescu, Karen O Dixon, Michael B Yaffe, Ioannis S Vlachos, Maria G Castro, Sean E Lawler, Gordon J Freeman, Vijay K Kuchroo, E Antonio Chiocca, Charles H Cook.

Oncolytic virotherapy represents a promising yet under-explored approach for precision cancer treatment, particularly when tailored to tumor-specific molecular profiles. Patients with high-grade isocitrate dehydrogenase (IDH) mutant astrocytomas have limited treatment options and poor prognoses. Here, we investigate the therapeutic efficacy of rQNestin34.5 v.2 (CAN-3110), an engineered oncolytic herpes simplex virus 1 (oHSV-1), in IDH1-R132H-mutant diffuse gliomas. We demonstrate that the IDH1-R132H mutation enhances glioma susceptibility to viral infection through upregulation of Nectin-1, the main HSV-1 entry receptor. Concurrently, IDH1-R132H-driven DNA hypermethylation suppresses interferon (IFN) signaling, creating a permissive microenvironment that facilitates viral replication and tumor cell apoptosis. In immunocompetent murine glioma models, intratumoral administration of rQNestin34.5 v.2 induces robust antitumor immune activation, including increased immune infiltration and systemic IFN-γ release. However, elevated expression of poliovirus receptor (PVR) and the immune checkpoint T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) on tumor-infiltrating leukocytes suggests a potential resistance mechanism to virotherapy. Combining rQNestin34.5 v.2 with TIGIT blockade enhances therapeutic efficacy compared to monotherapy, identifying IDH1-R132H as a potential predictive biomarker for oncolytic virotherapy response.

DOI: https://doi.org/10.1038/s41467-026-73974-5

Cell. 2026 Jun 15. pii: S0092-8674(26)00585-4. [Epub ahead of print]

The critical role of the endogenous immune compartment after CAR T cell therapy in recurrent GBM.

Nelson F Freeburg, Daniel Chafamo, Gayathri Konanur Gopikrishna, Regan M Murphy, Jacqueline J Peng, Shridhar Parthasarathy, Sydney Dumont, Edward G Estrada, Meghan T Logun, Yusha Sun, Xin Wang, Payal Grover, Jesse L Rodriguez, Daniel L Zhang, Kristen Park, Yao Fu, Nadine Ben Hamouda, Isaias Hernandez-Verdin, Lamia Lamrani, Kelly A Hicks, Natalie A Cooper, Christina Ekwegbara, Emma Grace Bawden, Joshua J Waterfall, Jaime Fuentealba, Marion Alcantara, John T Seykora, Stephen M Prouty, David Barrett, Esha Banerjee, Arin Cox, Charles-Antoine Assenmacher, Camilla Macia, Melinda Yin, Erica L Carpenter, Guo-Li Ming, Catherine Sautès-Fridman, Wolf H Fridman, Eric Tartour, E John Wherry, Sebastian Amigorena, Joseph A Fraietta, MacLean P Nasrallah, Hongjun Song, Tyler E Miller, Stephen J Bagley, Donald M O'Rourke, Zev A Binder, Cécile Alanio, Dana Silverbush.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with a median survival of under 15 months and no effective treatment after recurrence. A recent phase 1 trial of intracerebroventricular bivalent chimeric antigen receptor (CAR) T cells in recurrent GBM, registered at ClinicalTrials.gov (NCT05168423), showed promising responses, including tumor reduction and prolonged survival. However, relapse remains common. We performed in-depth profiling of longitudinal cerebrospinal fluid (CSF) and tumor samples from responders and non-responders to characterize immune dynamics following infusion. Our study reveals that, although CAR T cells activate post infusion across all patients, outcomes were defined by divergent remodeling of the endogenous immune landscape. Cytotoxic natural killer cell expansion characterized responders, whereas regulatory T cell expansion and abundant baseline immunosuppressive scavenger myeloid cells characterized non-responders. These findings indicate that host immune cells play a critical role in CAR T cell therapy for GBM, suggesting that combinatorial strategies modulating the endogenous immune compartment could improve next-generation treatments.

Keywords: CAR T cell therapy; NK cells; biomarkers; glioblastoma; immunology; immunotherapy; longitudinal dynamics; myeloid immunosuppression; regulatory T cells; single-cell transcriptomics; tumor microenvironment

DOI: https://doi.org/10.1016/j.cell.2026.05.026