bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2026–10–11
nine papers selected by
Oltea Sampetrean, Keio University
  1. Circadian biology in brain cancer diagnosis and treatment.
  2. Astrocytes support glioblastoma cells via tunnelling nanotubes.
  3. Targeting SLC38A5 Overcomes αPD-1 Immunotherapy Resistance by Alleviating Glutamine Competition Between Glioblastoma Cells and T Cells.
  4. Spatially restricted iron-metabolism-associated stress programs prime invasive mesenchymal glioblastoma states in human tissue-context models.
  5. Neoadjuvant PD1 plus CTLA-4 immune checkpoint blockade in surgically resectable recurrent glioblastoma: a randomized surgical window-of-opportunity trial.
  6. Augmenting Radiation Sensitivity by Targeting PAR-Dependent Replication Fork Vulnerability in IDH- Mutant Glioma.
  7. Targeting hypoxia-driven histone lactylation in myeloid cells synergizes with CD137 agonism to expand effector-like exhausted CD8+ T cells in glioblastoma.
  8. Longitudinal Surgical Modeling of Early Glioblastoma Recurrence Reveals Emergence of Margin-Associated Neural Programs.
  9. CEBPB integrates OSM signaling and eIF4G2-mediated alternative translation to configure enhancer landscape and sustain oncogenic CHI3L1 in glioblastoma.
  1. Neuro Oncol. 2026 Oct 08. pii: noag179. [Epub ahead of print]
    Circadian biology in brain cancer diagnosis and treatment.
    Sofia V Salvatore, Annika M Kaval, Erin M Gibson, Erik D Herzog.
      Glioblastoma (GBM), the most common and lethal primary brain cancer, has a median survival of 15 months. Despite repeated efforts over 20 years to introduce life-extending therapies, little has changed in the standard of care. Recent studies have revealed that GBM cells express daily rhythms in gene expression and sensitivity to chemotherapy. In this review, we highlight the role of circadian biology in GBM growth, and its potential applications to GBM diagnosis and treatment. The hallmarks of cancer often show daily variation. We emphasize opportunities to advance our understanding of glioblastoma pathophysiology by considering how brain tumors integrate into the host circadian system and respond to daily rhythms in neuronal, paracrine, or hormonal signals to promote growth. Circadian treatment strategies include disrupting daily rhythms in GBM cells, blocking their synchronization to the host, or finding best times of day for biopsy, surgery, radiation, or chemotherapy. We discuss an ongoing temozolomide chronotherapy trial in the context of recent evidence against chronotherapy and suggest ways to critically assess time-of-day effects in GBM. With over 500 active clinical trials for GBM, it is time to evaluate, and control for, circadian rhythms in care for brain cancer patients.
    Keywords:  MGMT; cancer neuroscience; chronotherapy; circadian; glioblastoma (GBM)
    DOI:  https://doi.org/10.1093/neuonc/noag179
  2. Nat Rev Neurol. 2026 Oct 09.
    Astrocytes support glioblastoma cells via tunnelling nanotubes.
    Ian Fyfe.
      
    DOI:  https://doi.org/10.1038/s41582-026-01281-0
  3. Cancer Res. 2026 Oct 05.
    Targeting SLC38A5 Overcomes αPD-1 Immunotherapy Resistance by Alleviating Glutamine Competition Between Glioblastoma Cells and T Cells.
    Zhuohao Liu, Jiani Lin, Tao Chen, Weimin Zhang, Ran Ye, Ying-Gui Yang, Na Li, Jiayi Zhou, Guisen Tan, Chenci Wang, Zhengwei Wang, Xiaoping Wu, Kenneth King-Yip Cheng, Jie Mao, Ming Gao, Jiacheng Liu, Xiaojuan Pei, Chi-Fai Ng, Yuliang Wang, Dinglan Wu.
      Despite the clinical success of programmed cell death protein 1 (PD-1) checkpoint blockade in many cancer types, its efficacy in glioblastoma remains notably limited, underscoring the critical need to uncover primary resistance mechanisms and identify synergistic therapeutic targets. To discover genes modulating αPD-1 immunotherapy response, we performed an in vivo CRISPR-Cas9 screen in immunocompetent mice bearing glioblastoma, which prioritized the glutamine (Gln) transporter SLC38A5 as a candidate modulator of αPD-1 immunotherapy efficacy. In human glioblastoma, SLC38A5 was significantly upregulated compared with normal brain tissue. Ablation of SLC38A5 did not impair glioblastoma cell intrinsic growth but profoundly sensitized glioblastoma to αPD-1 therapy in a CD8+ T cell-dependent manner, leading to enhanced anti-tumor immunity and tumor control. Mechanistically, SLC38A5 deficiency created a Gln-enriched tumor microenvironment by impairing Gln uptake of glioblastoma cells. This metabolic rewiring enhanced CD8+ T cell function via SLC1A5-dependent Gln utilization and promoted MHC-I-mediated antigen presentation in glioblastoma cells through a Gln-glutathione (GSH)-reactive oxygen species (ROS) axis. Furthermore, an SLC38A5-targeting nanobody was developed that efficiently accumulated in orthotopic glioblastoma and potentiated αPD-1 therapy to suppress brain tumor growth in vivo. Overall, this study establishes SLC38A5 as a metabolic immune regulator in glioblastoma and presents a promising Nb-based strategy for overcoming αPD-1 immunotherapy resistance.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-0774
  4. Neuro Oncol. 2026 Oct 08. pii: noag220. [Epub ahead of print]
    Spatially restricted iron-metabolism-associated stress programs prime invasive mesenchymal glioblastoma states in human tissue-context models.
    Christophe Petry, Ambra-Stella Boecke, Aso Omer Mohammed, Nishita S Ghariwala, Vatsal D Jariwala, Mohammad Al Shhab, Oliver Buchholz, Ioannis Vasilikos, Julia M Nakagawa, Andreas Vlachos, Jürgen Grauvogel, Mukesch J Shah, Roland Rölz, Marco Prinz, Ulrich G Hofmann, Jürgen Beck, Kevin Joseph, Vidhya Madapusi Ravi.
       BACKGROUND: Glioblastoma (GBM) recurrence is driven by invasive tumor cells that infiltrate surrounding brain tissue and evade surgical and therapeutic eradication. While dysregulated iron handling is a well-recognized feature of malignant cancers, its contribution to invasive GBM cell states in the physiological context of human cortical tissue remains poorly defined.
    METHODS: We performed multiregional single-nucleus RNA sequencing of human GBM specimens encompassing tumor core, tumor periphery, and infiltrated cortex to map iron-associated transcriptional programs validated by spatial transcriptomics. Correlative analyses were combined with functional validation using patient-derived GBM cell lines and human organotypic cortical slice cultures exposed to noncytotoxic iron supplementation to model iron-rich tumor microenvironments.
    RESULTS: Malignant cells from the tumor core exhibited coordinated upregulation of iron uptake and storage pathways alongside invasion-associated gene programs. At single-cell resolution, iron metabolism and invasion signatures were correlated, defining a core-enriched malignant subpopulation with mesenchymal-like transcriptional identity, stress-adaptive features, and angiogenic signaling that aggregate in specific spatial niches. Functionally, iron exposure altered migration in a cell-state-dependent manner and increased tumor growth and invasion in human cortical slice cultures. Increased VIM, MMP9, and HIF1A expression was consistent with activation of mesenchymal-like and stress-response programs, although mechanistic dependence was not tested.
    CONCLUSION: Iron-handling and invasion-associated programs co-occur in a core-enriched mesenchymal-like GBM state. In patient-derived cell and human cortical slice models, noncytotoxic particulate and soluble iron altered migration in a cell-state-dependent manner and increased tissue invasion. These findings support iron availability as a component of the microenvironment associated with invasive GBM phenotypes, while its necessity and underlying mechanism remain to be established.
    Keywords:  glioblastoma tumor core; human brain models; human glioblastoma model; iron-associated invasion in glioblastoma; mesenchymal-transition
    DOI:  https://doi.org/10.1093/neuonc/noag220
  5. Nat Commun. 2026 09 05. pii: 10560. [Epub ahead of print]17(1):
    Neoadjuvant PD1 plus CTLA-4 immune checkpoint blockade in surgically resectable recurrent glioblastoma: a randomized surgical window-of-opportunity trial.
    Lu Sun, Lauren F Markus, Julio C Sanchez, Thomas J Lai, Eudocia Quant Lee, Gang Li, Jiyoon Kim, Zian Zhuang, Brenda Acevedo, Richard G Everson, Ingo K Mellinghoff, Elisa Aquilanti, L Nicolas Gonzalez Castro, J Ricardo McFaline-Figueroa, Lakshmi Nayak, Rameen Beroukhim, Robert A Chong, Jacqueline Stone, Thomas Kaley, Lauren Schaff, Jessica Wilcox, Catharina Westergaard, Alyssa Russ, Maria Lavallee, Ugonma Chukwueke, Annick D Van den Abbeele, Michael Lim, Benjamin M Ellingson, David A Reardon, Timothy F Cloughesy, Robert M Prins, Patrick Y Wen.
      We conducted a randomized surgical window-of-opportunity trial ( NCT04606316 ) in recurrent, resectable glioblastoma. Between 2021 and 2024, 71 patients were screened, and 63 were randomized (intention-to-treat [ITT] population), and 58 received study treatment. Patients received pre-surgical immune checkpoint blockade (ICB) with dual anti-PD1 nivolumab + anti-CTLA4 ipilimumab (Arm 1), nivolumab alone (Arm 2), or placebo (Arm 3). Following surgery, Arms 1 and 3 received dual ICB, while Arm 2 continued nivolumab until progression or unacceptable toxicity. The primary endpoint, tumor-infiltrating lymphocyte (TIL) density, was met for Arm 1, as neoadjuvant dual ICB significantly increased TIL density compared with untreated control (Arm 3). As a secondary endpoint, median overall survival in the ITT population was 402 days (95% CI, 265-571) among patients who received dual ICB (Arms 1 and 3) and 273 days (95% CI, 166-506) for those assigned to nivolumab alone (Arm 2). No unanticipated toxicities were observed. Exploratory analyses showed that dual ICB elicited robust intratumoral and systemic immune activation, including increased interferon-related gene expression in blood. Higher TIL density and early systemic interferon-signature induction were associated with improved survival, whereas tumor mutational burden was not. Our results demonstrate pharmacodynamic activity of dual ICB in glioblastoma, with survival outcomes comparing favorably to similar studies.
    DOI:  https://doi.org/10.1038/s41467-026-77433-z
  6. bioRxiv. 2026 Aug 10. pii: 2026.08.08.743634. [Epub ahead of print]
    Augmenting Radiation Sensitivity by Targeting PAR-Dependent Replication Fork Vulnerability in IDH- Mutant Glioma.
    Yosuke Kitagawa, Ali Nasser, Ami Kobayashi, Ethan Wetzel, Lisa Melamed, Chia-Chen Chang, Hiroaki Nagashima, Julie J Miller, Hiroaki Wakimoto, Daniel P Cahill.
      Mutations in isocitrate dehydrogenase 1 ( IDH1 ) drive the early stages of gliomagenesis while simultaneously imposing replication stress that creates targetable vulnerabilities. Using both in vitro and in vivo models, we show that inhibition of poly(ADP-ribose) glycohydrolase (PARG) induces a poly(ADP-ribose) (PAR)-dependent augmentation of radiosensitivity in IDH1 -mutant glioma cells. Metabolic repletion of NAD + fails to rescue this effect, indicating that the vulnerability cannot be explained solely by NAD + depletion. Instead, PARG inhibition profoundly alters replication fork progression and S-phase kinetics in IDH1 -mutant cells. Mechanistically, ionizing radiation preferentially activates replication fork-associated damage response proteins DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and X-ray repair cross-complementing protein 1 (XRCC1) in IDH1 -mutant cells, a response partially reversed by pharmacologic inhibition of mutant IDH1 . Importantly, pharmacologic inhibition of DNA-PKcs with AZD7648 during irradiation disrupts fork-associated repair signaling and markedly enhances cytotoxicity in IDH1 -mutant glioma models. Together, these findings identify a PAR-dependent replication fork vulnerability that can be therapeutically exploited to selectively enhance radiosensitivity in IDH1 -mutant gliomas.
    Statement of significance: IDH -mutant gliomas harbor intrinsic replication stress yet lack targeted radiosensitization strategies. We identify a PAR-dependent replication fork vulnerability in which disruption amplifies radiation cytotoxicity by deregulating S-phase fork signaling. Pharmacologic DNA-PKcs inhibition exploits this dependency, providing a genotype-selective approach to enhance radiotherapy in IDH -mutant glioma.
    DOI:  https://doi.org/10.64898/2026.08.08.743634
  7. Neuro Oncol. 2026 Oct 08. pii: noag226. [Epub ahead of print]
    Targeting hypoxia-driven histone lactylation in myeloid cells synergizes with CD137 agonism to expand effector-like exhausted CD8+ T cells in glioblastoma.
    Alessio Ugolini, Fabio Scirocchi, Alessandra De Leo, Filippo Badii, Xiaoxian Liu, Angelica Pace, Luca D'Angelo, James K C Liu, Arnold B Etame, Pulak Ray, Marianna Nuti, Antonio Santoro, Aurelia Rughetti, Michael A Vogelbaum, Xiaoqing Yu, Filippo Veglia.
       BACKGROUND: Overwhelming presence of immunoregulatory myeloid cells and dysfunctional T cells is a major barrier to effective immunotherapies in glioblastoma (GBM). Therapeutic strategies that simultaneously address myeloid-driven immunosuppression and impaired T cell function are therefore needed to restore antitumor immunity in GBM.
    METHODS: We employed single-cell RNA sequencing, immunophenotyping, and functional analyses in an orthotopic murine GBM model (SB28) to investigate how hypoxia shapes the tumor immune microenvironment and limits CD8+ T cell responses. Pharmacologic hypoxia modulation using low-dose axitinib was combined with therapeutic intervention targeting CD137 in two GBM models (SB28, CT2A).
    RESULTS: Monocyte-derived macrophages (MDMs) and neutrophils constitute the most abundant and functionally immunosuppressive myeloid subsets within the GBM TME. Hypoxia reprogrammed MDMs and neutrophils into immunosuppressive cells, limiting the expansion of CD8+ T cells. Low-dose axitinib reduced intratumoral hypoxia, leading to altered glucose uptake and histone lactylation in MDMs and neutrophils, thereby impairing their immunosuppressive function and promoting the expansion of intratumoral PD-1+CD137+CD8+ T cells, specifically in the SB28 model. CD137 is largely expressed by effector-like exhausted CD8+ T cell subsets (EX-eff). Agonistic targeting of CD137, in combination with axitinib, robustly expanded EX-eff, which was accompanied by durable tumor regression, immunological memory, and long-term survival. Additionally, the abundance of PD-1+CD137+CD8+ T cells correlated with improved disease-free survival in patients with GBM.
    CONCLUSION: Together, these findings establish a rationale for a combinatorial strategy that couples myeloid cells targeting and CD8+ T cell activation to overcome immunotherapy resistance in GBM.
    Keywords:  exhausted T cells; glioblastoma; histone lactylation; hypoxia; immunosuppressive myeloid cells
    DOI:  https://doi.org/10.1093/neuonc/noag226
  8. Cancer Res. 2026 Oct 05.
    Longitudinal Surgical Modeling of Early Glioblastoma Recurrence Reveals Emergence of Margin-Associated Neural Programs.
    Adarsha P Malla, Matthew Flick, Jennifer R Fang, Xiaoxuan Fan, Chixiang Chen, Angad Beniwal, Chris Sereduk, Richard Drexler, Alexandros Poulopoulos, Michelle Monje, Pavlos Anastasiadis, Nhan L Tran, Jeffrey A Winkles, Graeme F Woodworth.
      Glioblastoma (GBM) is a lethal, treatment-resistant brain cancer characterized by diffuse brain invasion, complex neuron-glioma signaling, and cellular, molecular, and spatial heterogeneity. Surgery is the current mainstay of treatment, aimed at maximizing tumor cytoreduction, decompressing the brain to improve neurological function, and providing material for analyses to inform prognostication and adjuvant treatment selection. To accurately model GBM surgical resection and tissue sampling in preclinical animal models, we developed the Maximal Safe Intracranial Surgery (MSIS) system. MSIS integrated a miniaturized neurosurgical resection device and enabled a safe, tunable, and reproducible approach for intracranial tumor resection, multi-regional biopsy, and longitudinal tissue sampling in murine models, with stereotactic, sterile, and high-viability tissue collection. MSIS was applied across five distinct orthotopic brain tumor models to reproducibly generate histologically and radiologically representative models of post-surgical GBM. Similar to humans, increasing the extent of resection correlated with improved animal survival, and recurrent growth patterns varied significantly by model type. Transcriptional profiles of matched primary vs. post-surgical recurrent tumors revealed enrichment of margin-associated transcriptional states consistent with neuron-glioma signaling. Overall, the MSIS system offers opportunities to model the standard-of-care, dissect the spatial and temporal dynamics of GBM, and pair therapeutic discovery with contextual tumor pathobiology.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-5176
  9. Neuro Oncol. 2026 Oct 08. pii: noag246. [Epub ahead of print]
    CEBPB integrates OSM signaling and eIF4G2-mediated alternative translation to configure enhancer landscape and sustain oncogenic CHI3L1 in glioblastoma.
    Jiyang Liu, Ying Zhang, Xiaoping Yi, Long Xie, Xingze Huang, Zhipeng Zhu, Zhongyuan Zhang, Jing Wang, Suya Zheng, Yongjie Wang, Hangzhe Xu, Yue Yu, Zeming Tan, Tuan Zea Tan, H Phillip Koeffler, Ye Chen, Liang Xu.
       BACKGROUND: CEBPB is a critical driver of mesenchymal transformation and aggressiveness in glioblastoma (GBM). However, fundamental questions remain regarding its dynamic regulation within the GBM microenvironment and its precise mechanistic role in orchestrating the epigenetic and transcriptional reprogramming.
    METHODS: To decode the CEBPB cistrome and its role in chromatin remodeling in GBM, we performed an integrated analysis of CEBPB/H3K27ac ChIP-seq, CEBPB HiChIP, and RNA-seq. Transcriptional and translational control of CEBPB expression was delineated through enhancer profiling, bioinformatics analysis, siRNA screening, synthetic reporter assays, and immunoblotting. Functional investigations were conducted using patient-derived tumor spheroids, human and murine glioma cell lines, and xenograft/allograft murine models.
    RESULTS: We demonstrate that CEBPB is a super-enhancer-driven gene, with all three isoforms (LAP1, LAP2, LIP) over-expressed in primary GBM. Functional analyses reveal that LAP1 and LAP2 are essential for tumorigenesis, while LIP specifically promotes in vivo growth in a LAP1/LAP2-dependent manner. We further reveal that myeloid-derived OSM potently induces CEBPB expression through OSMR-STAT3-mediated transcription and a novel eIF4G2-dependent alternative translation process. Mechanistically, eIF4G2 directs selective LIP synthesis by engaging a specialized 3'UTR translation enhancer within the CEBPB transcript. Genetic ablation of EIF4G2 suppresses tumorigenicity, a phenotype fully rescued by LIP overexpression. Ultimately, CEBPB isoforms coordinately rewire the epigenetic landscape, remodeling super-enhancers and chromatin looping to establish an oncogenic transcriptional program that activates key effectors like CHI3L1.
    CONCLUSIONS: This work elucidates a pathogenic axis in glioblastoma wherein OSM signaling and eIF4G2-mediated alternative translation converge on CEBPB isoforms to enforce enhancer architectures and chromatin interactions for oncogenic transcription.
    Keywords:  Alternative translation; CEBPB; EIF4G2; LIP; epigenetic regulation
    DOI:  https://doi.org/10.1093/neuonc/noag246
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