bims-malgli 2026-09-13 papers

Issue of 2026–09–13
four papers selected by
Oltea Sampetrean, Keio University

Nat Commun. 2026 Aug 10. pii: 9577. [Epub ahead of print]17(1):

MALT1 protease inhibition restrains glioblastoma progression by reversing tumor-associated macrophage-dependent immunosuppression in mice.

MALT1 protease is an intracellular signaling molecule that promotes tumor progression via cancer cell-intrinsic and cancer cell-extrinsic mechanisms. MALT1 has been mostly studied in lymphocytes, and little is known about its role in tumor-associated macrophages. We show that MALT1 is expressed in glioblastoma (GBM)-associated macrophages. Mechanistically, GBM tumor cells induce a MALT1-NF-κB signaling axis in macrophages, leading to enhanced macrophage migration and polarization toward an immunosuppressive ('M2-like') phenotype. Inactivation of MALT1 protease promotes transcriptional reprogramming that reduces migration and restores a macrophage anti-tumor 'M1-like' phenotype. Preclinical in vivo analysis shows that MALT1 inhibitor treatment results in immuno-reactivity of GBM-associated macrophages and reduced GBM tumor growth. The addition of MALT1 inhibitor to temozolomide reduces immunosuppression in the tumor microenvironment, indicating that pharmacological inhibition of MALT1 protease may enhance the efficacy of chemotherapeutic. Thus, our findings suggest that MALT1 protease inhibition represents a promising macrophage-targeted immunotherapeutic strategy for the treatment of GBM.

DOI: https://doi.org/10.1038/s41467-026-76572-7

Neuro Oncol. 2026 Sep 08. pii: noag223. [Epub ahead of print]

Functional clustering within glioblastoma identifies a network-integrated subtype with improved survival.

Danting Zeng, Abraham Z Snyder, Ki Yun Park, Benjamin T Acland, Joshua S Shimony, Eric C Leuthardt.

BACKGROUND: Glioblastoma (GBM) is traditionally viewed as disrupting brain network connectivity. Recent evidence of tumor-neuron synaptic interactions suggests gliomas may actively engage with the brain. We hypothesized that GBM tumors contain functionally distinct intratumoral subregions that differentially couple with resting-state networks (RSNs) and carry prognostic significance.
METHODS: We applied fuzzy c-means clustering to resting-state fMRI data from 190 GBM patients to identify and count the number of intratumoral functional subregions. We used the participation ratio, a PCA-derived measure of signal dimensionality, as a continuous variable complement to cluster number. Cluster-level BOLD time series were correlated with seven canonical RSNs and compared to tumor location-matched voxels in 347 healthy subjects. Associations with survival and preoperative seizures were evaluated using Kaplan-Meier analysis, restricted mean survival time (RMST), multivariable Cox proportional hazards modeling, and multivariable logistic regression.
RESULTS: Fifty-two of 190 GBMs exhibited multiple intratumoral functional clusters. Multi-cluster tumors were associated with longer survival and higher seizure prevalence. Elevated RSN coupling was more prevalent in multi-cluster tumors as compared to single-cluster tumors, with elevated coupling strongly predicting multi-cluster status. Distinct clusters often showed preferential coupling to different RSNs.
CONCLUSIONS: A subset of GBM contains functionally distinct subregions that selectively engage large-scale brain networks, a pattern associated with favorable survival and increased seizure risk. These findings support a model in which certain tumors function as active participants within neurovascular networks, indicating a novel network-integrated subtype of GBM with implications for prognosis and disease staging.

Keywords: Glioblastoma; Intrinsic brain activity; Prognosis; Resting-state fMRI; Tumor-neuron interaction

DOI: https://doi.org/10.1093/neuonc/noag223

Nat Commun. 2026 Jul 31. pii: 9727. [Epub ahead of print]17(1):

Perioperative myeloid cell remodeling shapes CAR-T cell efficacy in glioblastoma.

Martin Pedard, Luis Castillo Cantero, Ali Ghasemi, Eliana Marinari, Caterina Mollica, Suzel Davanture, Julie Pernot, Valérie Widmer, Doron Merkler, Kristof Egervari, Karl Schaller, Philippe Bijlenga, Andrea Bartoli, Shahan Momjian, Mikael J Pittet, Valérie Dutoit, Denis Migliorini.

Glioblastoma (GBM) is characterized by a profoundly immunosuppressive tumor microenvironment (TME) that constrains the efficacy of chimeric antigen receptor (CAR)-T cell therapy. Here, we show that surgical resection in both male mice and human GBM ex vivo induces a rapid and sustained remodeling of the TME, marked by upregulation of TREM2 in myeloid cells followed by emergence of T cell exhaustion-like phenotypes. In male mice, targeting TREM2 reshapes the perioperative TME and potentiates tumor antigen-specific CAR-T cell responses, improving intratumoral persistence, proliferation, and effector differentiation, and resulting in enhanced survival. In parallel, we identify the timing of CAR-T cell administration as a critical determinant of therapeutic outcome, with neoadjuvant outperforming adjuvant treatment by preserving CAR-T cell effector function in mice. These findings establish perioperative myeloid cell remodeling and treatment timing as key determinants of CAR-T cell efficacy in GBM.

DOI: https://doi.org/10.1038/s41467-026-76206-y

Neuro Oncol. 2026 Sep 09. pii: noag225. [Epub ahead of print]

EFTUD2-Regulated Alternative Splicing of MSH5 Drives Radioresistance in Recurrent IDH-Mutant Glioma.

Qiu He, Runxin Wu, Xiaozhou Yu, Xiao Song, Maya Walker, Deanna Tiek, Tongchao Jiang, Xiao-Nan Li, Chengtao Her, Bo Hu, Shi-Yuan Cheng.

BACKGROUND: Recurrent IDH-mutant gliomas frequently acquire increased radioresistance, leading to poorer outcomes. Their underlying mechanisms, however, remain largely unknown. We hypothesize that dysregulated RNA alternative splicing (AS) during IDH-mutant glioma recurrence contributes to the enhanced radioresistance by influencing critical cellular pathways.
METHODS: RNA sequencing of paired primary and recurrent IDH-mutant gliomas were analyzed to identify recurrence-associated AS events. Functional effects were assessed in patient-derived glioma stem cells using RNA interference and CRISPR-dCas13-mediated isoform switching. Candidate upstream RNA-binding proteins and antisense oligonucleotide (ASO)-based therapeutic strategies were evaluated in vitro and in vivo.
RESULTS: We identified differentially spliced MutS homolog 5 (MSH5) isoforms between primary and recurrent IDH-mutant gliomas. Primary gliomas predominantly expressed an exon 11/12-skipped MSH5 transcript, whereas recurrent tumors largely retained the full-length isoform. Exon 11/12 skipping introduced a premature termination codon, leading to nonsense-mediated decay and diminished MSH5 expression in primary tumors. Further analyses identified elongation factor Tu GTP binding domain containing 2 (EFTUD2) as an upstream splicing regulator that was upregulated in recurrent tumors and promoted exon 11/12 inclusion, thereby maintaining MSH5 expression and enhancing the repair of radiation-induced DNA double-strand breaks. Inducing MSH5 exon 11/12 skipping with CRISPR-dCas13 or inhibiting EFTUD2 with ASOs reduced MSH5 expression, impaired DNA repair, and sensitized recurrent IDH-mutant glioma to radiotherapy in vitro and in vivo.
CONCLUSIONS: These findings identify an EFTUD2-MSH5 splicing axis that contributes to radioresistance in recurrent IDH-mutant glioma. Therapeutic disruption of this splicing program may represent a strategy to enhance the radiation response in recurrent IDH-mutant glioma.

Keywords: Alternative splicing; EFTUD2; IDH-mutant glioma; MSH5; Radiotherapy

DOI: https://doi.org/10.1093/neuonc/noag225