bims-malgli 2026-08-23 papers

Issue of 2026–08–23
six papers selected by
Oltea Sampetrean, Keio University

Neuro Oncol. 2026 Aug 19. pii: noag193. [Epub ahead of print]

Abexinostat attenuates temozolomide-resistant glioma stem cells.

Balaji Perumalsamy, Raghupathy Vengoji, Anand Thiraviyam, Indumati Ramireddy, Poonam Yadav, Ashu Shah, Kavita Mallya, Afshin Salehi, Sushil Kumar, Maneesh Jain, Moorthy P Ponnusamy, Surinder K Batra, Nicole Shonka.

BACKGROUND: Glioblastoma (GBM) is the most common adult primary brain malignancy. Recent studies demonstrate that temozolomide (TMZ) facilitates the persistence of quiescent glioma stem cells (GSCs), which are responsible for GBM recurrence. An ideal therapy should eradicate both proliferating cells and GSCs. Abexinostat (Abx), a histone deacetylase inhibitor, was identified through connectivity mapping to target the specific GBM signature. Here, we demonstrate the anti-proliferative effect of Abx on both differentiated cells and GSCs.
METHODS: Using patient-derived tumor cultures (PDCs) to test Abx in vitro, ATAC-seq identified chromatin accessibility. Single-spheroid and alkaline phosphatase staining assays were used to test stem cell self-renewal. Aldehyde dehydrogenase activity distinguished mesenchymal GSCs. The efficacy of Abx with TMZ was evaluated in GSC-expressing CK9751 PDC and mesenchymal patient-derived xenografts (PDXs).
RESULTS: In PDCs (CK9495 and CK9751), Abx decreased the DNA repair machinery (RAD51, CHK1, Ku70, and MGMT) and induced apoptosis. Focused ATAC-seq analysis for promoters of DNA repair (RAD51, Ku70, CHK1, and BRCA1) and stemness (CD44, KLF4, c-Myc, and BMI1) revealed Abx decreased chromatin accessibility. Abx decreased stem cell self-renewal and reduced the mesenchymal stem cell signature (CD44, ALDH1A3 expression, and ALDH1 activity) in vitro GBM models. Abx reduced tumor growth and stemness markers in CK9751 PDC and mesenchymal PDXs.
CONCLUSION: Abx reduced both DNA repair machinery and GSC markers by decreasing chromatin accessibility. Abx reduced tumor growth and mesenchymal GSCs in vitro and in vivo in GBM PDC and PDX models, supporting Abx's potential to prevent GSC-mediated therapy resistance and improve patient survival.

Keywords: ATAC-seq; DNA repair machinery; Mesenchymal glioma stem cells; glioblastoma; temozolomide resistance

DOI: https://doi.org/10.1093/neuonc/noag193

Res Sq. 2026 Aug 05. pii: rs.3.rs-10472790. [Epub ahead of print]

A dual pronged approach to cancer immune exclusion: tumor-derived LAIR-1 simultaneously drives fibrosis and blocks immune recruitment in glioma.

Maria Luisa Varela, Henry Kast, Molly West, Marisa Rose, Daiana Perez Visñuk, Mary Violet Springer, Sadhakshi Raghuram, Ziwen Zhu, Yichen Wang, Brandon McClellan, Andrea Comba, Bhuvna Murthy, Fateme Karimi Hafshejani, Hend AlMunaidi, Marta Edwards, Joshua Welsh, Maria G Castro, Pedro R Lowenstein.

Glioblastoma is among the most lethal human malignancies. Immune-based therapies have failed due to a strong immunosuppressive tumor microenvironment (TME)1. We uncovered that LAIR-12 expressed by tumor cells simultaneously drives TME fibrosis and inhibits migration of immune cells to brain tumors, thus achieving powerful immune exclusion3. We demonstrate that glioma-cell-specific LAIR-1 knockdown (KD), but not LAIR-1 KD from host cells, significantly extends survival in an immune-dependent manner. Glioma-cell-specific LAIR-1 signals through SHP2 to activate JNK -which on one hand sustains high levels of Lysyl Oxidase-Like 1 and collagen I to block immune cells' entry- and on the other hand suppresses STAT3 signaling. In the absence of LAIR-1, gliomas' collagen-dense ECM becomes disassembled and, through STAT3-driven upregulation of ADAM10 and ADAM17, promotes release of CXCL16, and recruitment of NK cells and cytotoxic T cells. Combining LAIR-1 KD with immune-stimulatory gene therapy4 achieved 100% long-term survival with durable immunological memory in immunocompetent mice. Pharmacological SHP2 inhibition in LAIR-1 WT mouse and human glioma cells recapitulated the LAIR-1 KD molecular phenotype and similarly potentiated gene therapy. These findings define LAIR-1 as a tumor-cell-intrinsic pro-fibrotic and immunosuppressive checkpoint and identify the LAIR-1>SHP2>JNK>CXCL16 and/or LOXL1 axis as a therapeutic target for sensitizing glioma to immunotherapy.

DOI: https://doi.org/10.21203/rs.3.rs-10472790/v1

Nat Rev Clin Oncol. 2026 Aug 19.

Exploring the landscape of targetable alterations in patients with glioblastoma.

Elisa Aquilanti, Mehdi Touat, Pim French, Antonio Iavarone, David Capper, Marjolein Geurts, Rifaquat Rahman, Roel Verhaak, Matthias Preusser, Martin van den Bent, Patrick Y Wen.

Glioblastomas remain the most lethal primary brain tumour in adults, with targeted therapies delivering only limited benefit despite deep molecular characterization. Several targeted drugs have received regulatory approval for low-grade gliomas, although progress in glioblastomas remains constrained by, among other aspects, extensive intratumoural heterogeneity, pathway redundancy, cellular plasticity and limited drug delivery to the central nervous system. Some of these challenges might be mitigated through strategies that enhance blood-brain penetration, including focused ultrasonography, convection-enhanced delivery, efflux avoidance and chemical modifications. Improved tumour profiling through multiregional sampling, prioritization of truncal dependencies and the development of novel therapeutic modalities, such as antibody-drug conjugates and theranostics, might also further improve outcomes. In this Review, we summarize the therapeutic landscape of targeted therapies in glioblastomas, spanning major target classes including receptor tyrosine kinases, intracellular signalling proteins, cell-cycle dysregulation and synthetic-lethal vulnerabilities. We also examine emerging strategies targeting genome integrity and telomeres, epigenetic modulators, and tumour-neural circuitry. Furthermore, we highlight tumour heterogeneity and extrachromosomal DNA dynamics as key drivers of oncogene amplification and therapeutic resistance as well as the roles of novel clinical trial designs and liquid biopsy-based monitoring strategies. Lastly, we discuss pathway-based glioblastoma classification and master kinase mapping as methods for aligning drugs with functional tumour states.

DOI: https://doi.org/10.1038/s41571-026-01190-7

Nat Rev Cancer. 2026 Aug 20.

Brain barriers at the crossroads of glioma immune surveillance and immunotherapy response.

Britta Engelhardt, Michael Platten.

Immunotherapies have substantially advanced cancer treatment; however, their efficacy in gliomas remains limited. This observation cannot be fully explained by tumour-intrinsic factors and may rather be linked to the distinct relationship between the central nervous system (CNS) and the immune system, commonly described as CNS immune privilege. CNS immune privilege is maintained by specialized brain barriers that divide the CNS into compartments with distinct accessibility to immune mediators and immune cells. Although maintaining homeostasis of the CNS parenchyma, these brain barriers direct CNS immune surveillance to the subarachnoid and the perivascular spaces at the CNS borders. Consequently, tumours arising in the CNS parenchyma are shielded from effective immune detection, limiting the efficacy of immunotherapies such as immune checkpoint inhibitors, cancer vaccines and adoptive T cell therapies such as chimeric antigen receptor (CAR) T cells and T cell receptor (TCR) transgenic T cells by restricting their access. Importantly, emerging evidence also indicates that gliomas actively remodel brain barrier functions to reinforce immune evasion. Failure to adequately consider brain barrier function in the context of immunotherapy strategies and clinical trial design therefore represents a major gap in the field. Understanding the orchestrated function of the brain barriers as neuroimmunological interfaces is essential for enhancing immune surveillance and improving immunotherapy responses in patients with brain tumours.

DOI: https://doi.org/10.1038/s41568-026-00960-w

J Clin Invest. 2026 Aug 18. pii: e200550. [Epub ahead of print]

Convection-enhanced delivery of dexamethasone in glioma models suppresses myeloid inflammation while avoiding systemic toxicities.

Dexamethasone is widely used to control cerebral edema and inflammation in glioblastoma, but its benefits are limited by systemic toxicities and adverse prognostic associations. We evaluated local administration of dexamethasone via convection-enhanced delivery (CED) to maximize intratumoral anti-inflammatory effects by increasing local corticosteroid exposure while minimizing systemic exposure. In two glioma mouse models, continuous intraparenchymal infusion of dexamethasone was well tolerated with no adverse effects. Pharmacokinetic analyses supported preferential intratumoral distribution and reduced systemic exposure with CED compared with systemic dosing. Single-nucleus RNA sequencing (snRNA-seq) and immunohistochemistry showed attenuation of glioma-associated inflammation with downregulation of reactive microglial/macrophage programs and reduced tumor-infiltrating myeloid cells with a morphology consistent with a less activated state. Experiments in human induced pluripotent stem cell (iPSC)-derived microglia confirmed that dexamethasone directly suppresses inflammatory gene expression, indicating a conserved mechanism across species. This inflammatory suppression was recapitulated in both immortalized microglial (HMC3) and macrophage (THP1) cell lines. These findings suggest that localized dexamethasone delivered by CED reprograms the glioma immune microenvironment and achieves control of inflammation without the systemic adverse effects associated with standard systemic dexamethasone therapy. This clinically translatable strategy may improve symptom management and provide a platform for integrating local immunomodulation with future glioblastoma therapies.

Keywords: Brain cancer; Inflammation; Macrophages; Oncology

DOI: https://doi.org/10.1172/JCI200550