bims-malgli 2026-07-12 papers

Issue of 2026–07–12
four papers selected by
Oltea Sampetrean, Keio University

Sci Rep. 2026 Jul 10.

TAZ mediates enhancer reprogramming blocks neuronal differentiation in glioma stem-like cells.

Alessandra Audia, Mahinur Mattohti, Visweswaran Ravikumar, Luciano Garofano, Ahmed Emam, Tiffany Tang, Emily Z Huie, Takashi Oizumi, Domenica Stella Toso Villanueva, Nazanin Esmaeili Anvar, Angel Adrian Garces, Brian D Vaillant, Arvind Rao, Antonio Iavarone, Hiroshi Katayama, Kunal Rai, Krishna P Bhat.

Brain tumors such as glioblastomas contain hierarchically organized, tumor-propagating glioma stem-like cells (GSCs). A non-cytotoxic strategy to limit the growth of these cells involves promoting terminal differentiation and mitotic exit; however, these approaches have remained largely unsuccessful. In this study, we combined in silico, in vitro, and in vivo methods to determine the influence of transcriptional coactivator with PDZ-binding motif (TAZ), an oncogenic transcription coactivator, in regulating cellular hierarchies in GSCs. We found that TAZ inhibits the neuronal lineage pathway in gliomas and GSCs, and that TAZ expression inversely correlates the master transcription factors (TFs) that drive neuronal fate. Overexpression of TAZ in GSCs disrupted neuronal differentiation by restructuring the enhancer landscape and downregulating essential master TFs associated with neurogenesis, such as OLIG2 and ASCL1. These effects were mediated by histone deacetylases 1 HDAC1). Knockdown of TAZ and its paralog YAP caused aberrant neuronal differentiation of GSCs. Thus, directed neuronal fate can be achieved by blocking TAZ/HDAC complexes, uncovering a novel mode of cellular differentiation that can be utilized as a non-cytotoxic therapeutic strategy for malignant gliomas.

Keywords: Enhancer reprograming; Glioma stem-like cells; Neuronal differentiation; TAZ

DOI: https://doi.org/10.1038/s41598-026-61249-4

Nat Med. 2026 Jul 10.

Anti-LAG-3 with or without anti-PD-1 in recurrent glioblastoma: a phase 1 trial.

Lymphocyte activation gene 3 (LAG-3) is an immune checkpoint implicated in T cell exhaustion and a potential therapeutic target in glioblastoma (GBM). We conducted a multicenter, open-label, phase 1 study with sequential allocation to evaluate the safety and preliminary activity of the anti-LAG-3 antibody relatlimab, administered alone or with the anti-programmed cell death protein 1 (PD-1) antibody nivolumab, in patients with recurrent GBM. Forty-six patients were treated (23 per cohort). The primary endpoint of safety was met, with maximum tolerated doses of 800 mg relatlimab for monotherapy and 160 mg relatlimab/240 mg nivolumab for combination therapy. Treatment-related grade 3-4 adverse events occurred in 6 of 23 patients receiving combination therapy and were not observed with monotherapy. Neoadjuvant administration was associated with increased intratumoral CD8+ T cell infiltration for both monotherapy and combination therapy. Exploratory analyses suggested that tumors with elevated baseline interferon signaling and increased T cell clonality were enriched among patients with durable responses to combination therapy. Twelve-month overall survival was 34.8% with relatlimab alone and 52.2% with combination therapy; however, this study was not designed to assess efficacy. These findings demonstrate an acceptable safety profile and provide preliminary immunologic and clinical signals supporting further evaluation of LAG-3 blockade in GBM. ClinicalTrials.gov identifier: NCT02658981 .

DOI: https://doi.org/10.1038/s41591-026-04475-7

Cancer Cell. 2026 Jul 09. pii: S1535-6108(26)00294-1. [Epub ahead of print]

Stressed bones and glioblastoma.

Manuel Valiente.

Chronic stress has long been associated with poor cancer outcomes, yet the mechanisms linking systemic stress responses to glioblastoma progression remain poorly understood. In this issue of Cancer Cell, Yang et al. identify a stress-induced brain-bone marrow axis that rewires monocyte differentiation toward pro-tumorigenic macrophages, revealing unexpected therapeutic opportunities in glioblastoma.

DOI: https://doi.org/10.1016/j.ccell.2026.06.007

J Clin Oncol. 2026 Jul 08. JCO2502463

Intracranial Injection of Investigational Ex Vivo Expanded and Activated Gamma-Delta T Cells Engineered With a Methylguanine-DNA Methyltransferase-Expressing Lentivector in Patients With Primary Glioblastoma.

Louis B Nabors, Mina Lobbous, Xiaosi Han, John Fiveash, Antonio Di Stasi, Kate Rochlin, Robert Oster, Thirumaine Pillay, Ryan Miller, Darshan S Chandrashekar, Mariska Ter Haak, William Ho, Lawrence S Lamb.

PURPOSE: We developed a novel approach to treat newly diagnosed glioblastoma (GBM) using genetically modified gamma-delta (γδ) T cells following the forced upregulation of stress-associated targets on tumor cells. We leveraged the temozolomide (TMZ)-induced activation of the DNA damage response pathway to transiently upregulate the natural killer ligand (NKG2D-L) targets on GBM. Manufactured γδ T cells are engineered to be resistant to alkylating chemotherapies, including TMZ, through insertion of a methylguanine-DNA methyltransferase (MGMT)-expressing lentivector (DeltEx drug-resistant immunotherapy-DRI).
METHODS: A total of 23 patients were enrolled, and 13 were treated (62% male; median age 66 years [range, 21-75]; 92% isocitrate dehydrogenase wild type (IDH-WT), 54% MGMT unmethylated, 46% subtotal resection). Cohorts 1, 2, and 3 received 1, 3, or up to 6 doses, respectively (1 × 107 DRI cells/dose), using a Rickham catheter, which was placed into the resection cavity. The DRI cells were dosed in combination with 150 mg/m2 intravenous (IV) TMZ once per day on Day (D) 1 of each maintenance cycle, which was followed by 4 days of oral TMZ.
RESULTS: No dose-limiting toxicities were seen nor were any occurrences of cytokine release syndrome (CRS) or neurotoxicity (immune effector cell-associated neurotoxicity syndrome) observed. The median follow-up of patients who received DRI γδ T cells was 15.6 months. For Cohort 1 patients who received a single dose of DRI γδ T cells, the median progression-free survival (mPFS) was 8.0 months; the median PFS was 9.9 months for all patients and 16.1 months for patients who received repeated doses in Cohorts 2 and 3. The median overall survival for all patients was 15.6 months.
CONCLUSION: To date, all patients had manageable toxicity with outpatient treatment and a continued encouraging trend in outcomes from repeated investigational treatments with intracranially delivered, longitudinal DRI γδ T cells.

DOI: https://doi.org/10.1200/JCO-25-02463