bims-malgli 2026-06-28 papers

bioRxiv. 2026 Jun 11. pii: 2026.06.09.730969. [Epub ahead of print]

Glioblastoma-derived extracellular vesicles released after radiation promote cognitive impairment through NFκB-mediated microglial activation.

Sara Macias Palacio, Nicole Rummel, James Campbell, D Allan Butterfield, Subbarao Bondada, Chi Wang, Abu Saleh Mosa Faisal, John Villano, Bjoern Bauer, Daret St Clair, Luksana Chaiswing.

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. Cognitive impairment is a common sequela in glioblastoma survivors, yet the underlying mechanisms remain poorly understood. Extracellular vesicles (EVs) derived from glioblastoma are established mediators of intercellular signaling within the tumor microenvironment. Here, we investigated whether GBM-derived EVs released after radiation treatment (RT-EVs) regulate cognitive function. Treatment with RT-EVs was associated with cognitive deficits and neuroinflammatory responses in vivo. In vitro, RT-EVs activated the NFκB pathway and induced the release of neurotoxic H 2 O 2 . Importantly, NFκB p50 knockdown abolished the H 2 O 2 release previously triggered by RT-EVs, demonstrating mechanistic dependence on NFκB signaling. Collectively, these findings identify GBM-derived RT-EVs as critical mediators of cognitive impairment through NFκB-dependent redox imbalance. EV-driven redox dysregulation may therefore represent a therapeutic target to mitigate GBM-associated cognitive dysfunction.
Highlights: Radiation induces the release of glioblastoma-derived EVs that are biologically different from those released under non-irradiated conditions.EVs released from glioblastoma after radiation are sufficient to impair cognition EVs from irradiated glioblastoma can activate microglia via NFκB and induce production of neurotoxic H 2 O 2.

DOI: https://doi.org/10.64898/2026.06.09.730969

Nat Commun. 2026 Jun 25.

Glioma-intrinsic MAPK/ERK signaling promotes immunotherapy efficacy through T cell infiltration and interferon responses.

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 BRAFV600E 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.

DOI: https://doi.org/10.1038/s41467-026-74124-7

Nat Cancer. 2026 Jun 23.

GABA signaling activation drives glioblastoma progression in female mice through myeloid-derived suppressor cells.

Sex differences in immune responses impact cancer outcomes and treatment response, including in glioblastoma (GBM). However, host factors underlying distinct immune-cancer interactions are poorly understood. Here we identify γ-aminobutyric acid (GABA) as a female-specific driver of GBM-promoting immune response. We demonstrated that GABA receptor B (GABBR) signaling enhances the T cell suppressive function of granulocytic myeloid-derived suppressor cells (gMDSCs) from female mice by upregulating the cationic amino acid transporter 2-L-arginine-nitric oxide synthase 2 (NOS2) pathway. GABBR agonism promotes GBM growth in female preclinical models through gMDSCs, while GABBR antagonism extends survival and reduces NOS2 in tumor-infiltrating gMDSCs only in female mice. Immune cells from female participants with GBM have enriched GABA transcriptional signatures and a higher GABA concentration compared to male counterparts. Collectively, these results highlight the sex-specific immunomodulatory role of GABA in tumorigenesis, supporting future assessment of GABA pathway inhibitors for cancer immunotherapy.

DOI: https://doi.org/10.1038/s43018-026-01192-5

Neuro Oncol. 2026 Jun 25. pii: noag142. [Epub ahead of print]

Selective histone deacetylase inhibition as a therapeutically relevant strategy in H3K27M-glioma.

BACKGROUND: Diffuse midline glioma (DMG) is a lethal pediatric brain tumor, driven by profound epigenetic dysregulation, raising the possibility that targeting epigenetic regulators such as histone deacetylases (HDACs) could provide a therapeutic benefit. However, despite preclinical activity, currently available HDAC inhibitors have shown limited clinical translation due to poor central nervous system (CNS) penetration and a lack of HDAC isoform selectivity.
METHODS: We combined CRISPR/Cas9 screening and pharmacologic HDAC inhibition to identify isoform-specific dependencies in DMG cell lines. Mechanistic studies were performed using bulk RNA-seq and HiChIP, and therapeutic efficacy was evaluated in orthotopic patient-derived xenograft mouse models.
RESULTS: We identify that the nuclear-localized Class I HDAC isoforms are dependencies in DMG and demonstrate that HDAC2 represents a selective dependency that is highly expressed in patient tumors. We further identify a CNS-penetrant HDAC inhibitor, Compound 26, with preferential HDAC1/2 isoform selectivity. Transcriptomic and chromatin conformation analyses reveal that Compound 26 induces rapid transcriptional reprogramming, restores physiologic pontine histone patterns, and induces cell cycle arrest through chromatin reorganization. Consistent with these effects, Compound 26 slows DMG growth in vitro and in orthotopic in vivo models.
CONCLUSIONS: Our findings establish HDAC2 as a critical and therapeutically actionable dependency in DMG. Genetic or pharmacological targeting of HDAC2 disrupts DMG chromatin architecture and induces cell cycle arrest. The HDAC1/2-selective inhibitor Compound 26 exhibits favorable CNS-penetration, tolerability, and antitumor activity in disease-relevant patient-derived xenograft models. Collectively, these data support isoform-selective HDAC inhibition as a rational strategy to overcome the translational limitations of pan-HDAC inhibitors in DMG.

Keywords: Diffuse intrinsic pontine glioma; Diffuse midline glioma; epigenetics; histone deacetylase inhibitor; pediatric brain tumor

DOI: https://doi.org/10.1093/neuonc/noag142