bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2026–03–08
fourteen papers selected by
Oltea Sampetrean, Keio University
  1. Inhibiting advillin in glioblastoma.
  2. Tumor-intrinsic chromatin programs enforce immune evasion in glioblastoma.
  3. Redefining the immune microenvironment of gliomas in the era of single-cell genomics.
  4. 20 years of the Stupp protocol: confronting stagnation in glioblastoma therapy.
  5. Lipocalin 2 orchestrates resistance to ferroptosis via AXL.
  6. The glioblastoma GBMdrug1000 dataset resource provides directions for future small molecule drug discovery.
  7. Targeting leucine-rich repeat kinase 2 overcomes resistance to oncolytic herpes simplex virus-based therapies in glioblastoma.
  8. Downfield magnetic resonance signals serve as endogenous imaging biomarkers of nucleotide metabolism in glioma.
  9. Contrast-free identification of glioma blood-brain barrier status via generative diffusion AI and non-contrast MRI.
  10. Nucleoli-localized KANSL2 as an epigenetic regulator of ribosome biogenesis in glioblastoma cells.
  11. Functionally distinct ALK and ROS1 fusions detected in infant-type hemispheric gliomas converge on STAT3 and SHP2 activation.
  12. The multifunctional RNA helicase DDX39A drives glioblastoma progression by modulating WISP1 alternative splicing that induces an immunosuppressive macrophage polarization.
  13. Spatial Transcriptomics Characterisation of Radionecrotic Changes in Glioblastoma Patients.
  14. GITR activation potentiates anti-tumor immunity of tumor-infiltrating lymphocytes expanded from glioblastoma by rescuing exhaustion.
  1. Nat Rev Drug Discov. 2026 Mar 03.
    Inhibiting advillin in glioblastoma.
    Sarah Crunkhorn.
      
    DOI:  https://doi.org/10.1038/d41573-026-00037-1
  2. J Clin Invest. 2026 Mar 02. pii: e203222. [Epub ahead of print]136(5):
    Tumor-intrinsic chromatin programs enforce immune evasion in glioblastoma.
    Raymond Sun, Chao Gao, Rongze Olivia Lu.
      Immunotherapy has shown limited efficacy in glioblastoma (GBM), reflecting profound immune evasion and an immunosuppressive microenvironment. In this Commentary, we highlight recent work by Zhang and colleagues identifying the transcription factor OLIG2 as a central mediator of immune evasion in GBM. Though OLIG2 has an established role in promoting GBM progression through its effects on glioma stem-like cells (GSCs), Zhang et al. demonstrated a further role for OLIG2 in suppressing antitumor immunity: in human GSCs and GSCs from mouse models of GBM, OLIG2 expression epigenetically repressed the interferon-responsive chemokine CXCL10, thereby limiting cytotoxic T cell infiltration. These findings provide a mechanistic explanation for immune resistance in GBM and support targeting tumor-intrinsic chromatin programs to enhance responses to immunotherapy.
    DOI:  https://doi.org/10.1172/JCI203222
  3. Neurooncol Adv. 2026 Mar;8(Suppl 1): i4-i16
    Redefining the immune microenvironment of gliomas in the era of single-cell genomics.
    L Nicolas Gonzalez Castro, Vrishabhadev Sathish Kumar, Mario L Suva, Tyler E Miller.
      Infiltrating gliomas are the most common primary malignant brain tumor and remain universally fatal. Over the past decade, advances in single-cell technologies, including single-cell RNA sequencing, have significantly advanced our understanding of malignant cells in glioma. These efforts have revealed extensive transcriptional heterogeneity and plasticity within glioma cells, identifying distinct cellular states and developmental programs that are discussed elsewhere. Recognizing that the tumor microenvironment constitutes sometimes more than half of the cells in gliomas, and that it has a profound impact on glioma cellular states, recent research has focused on non-malignant cells and their interactions with cancer cells. The present review reflects on lessons learned from single-cell genomics on the tumor immune microenvironment (TIME) of gliomas, as the dominant component of the tumor outside of the malignant cells and explores implications for developing effective immunotherapies.
    Keywords:  cell RNA sequencing; glioma; single; tumor immune microenvironment (TIME)
    DOI:  https://doi.org/10.1093/noajnl/vdaf087
  4. Lancet Oncol. 2026 Mar;pii: S1470-2045(25)00705-3. [Epub ahead of print]27(3): 277-280
    20 years of the Stupp protocol: confronting stagnation in glioblastoma therapy.
    Mustafa Khasraw, Emma Pristo, Roger Stupp.
      
    DOI:  https://doi.org/10.1016/S1470-2045(25)00705-3
  5. Cell Rep. 2026 Feb 27. pii: S2211-1247(26)00043-4. [Epub ahead of print]45(3): 116965
    Lipocalin 2 orchestrates resistance to ferroptosis via AXL.
    Sabrina Z Wang, J Payton Timken, Ellen S Hong, Sehaj Kaur, Eli Newby, Kristen E Kay, Erin E Mulkearns-Hubert, Daniel J Silver, Juyeun Lee, Joshua B Rubin, James R Connor, Loic P Deleyrolle, Deanna Tiek, Andrew Dhawan, Justin D Lathia.
      Glioblastoma (GBM) remains a lethal tumor, largely due to robust mechanisms that prevent effective induction of cell death. Ferroptosis, a form of iron-dependent cell death, is a promising vulnerability in GBM. Here, we demonstrate that lipocalin-2 (LCN2) suppresses ferroptosis in GBM cells via the receptor tyrosine kinase AXL. LCN2 was elevated in GBM cells compared to lower-grade tumor and non-transformed cells, and Lcn2 knockdown impaired GBM cell fitness and growth in vitro and in vivo. Mechanistically, Lcn2 knockdown triggered ferroptosis, which was specifically rescued with ferroptosis inhibitors but not apoptosis or necroptosis inhibitors. Lcn2 knockdown reduced AXL phosphorylation, which was elevated in GBM patient tumors relative to non-tumor tissue. Notably, the combination of Lcn2 knockdown and pharmacological AXL inhibition extended survival compared to Lcn2 knockdown alone. Taken together, these data reveal a link between LCN2-mediated suppression of ferroptosis with AXL phosphorylation and support this axis as a potential therapeutic target for GBM.
    Keywords:  AXL; CP: cancer; cell death; glioblastoma; lipocalin-2
    DOI:  https://doi.org/10.1016/j.celrep.2026.116965
  6. Neurooncol Adv. 2026 Jan-Dec;8(1):8(1): vdag030
    The glioblastoma GBMdrug1000 dataset resource provides directions for future small molecule drug discovery.
    Lavinia-Lorena Pruteanu, Olivier J M Béquignon, Yoran Broersma, Andreas Bender, Saleh M Ibrahim, David S Bailey, Bart A Westerman.
       Background: We previously created a glioblastoma (GBM) DrugBank containing curated information on chemical structure, molecular target activity, and chemical biology for 500 compounds. This study expands the dataset to 1103 compounds, including molecular bioactivity, cellular dose-response, CRISPR-Cas9 knockout data, potential toxicity, and links to clinical trials and patents.
    Methods: We gathered information from literature on compounds and models, allowing direct comparisons between compounds, their targets, and biological effects. We also included our own dose-response and drug-induced gene expression data across various glioblastoma cell culture models. Compounds were curated for their effect in preclinical GBM models, and these parameters were projected onto an ECFP_6-based UMAP visualization.
    Results: The visualization facilitates comparisons of bioactivities, CRISPR-Cas9 effects in GBM, and potential toxicity in nontransformed models. The analysis highlights the strengths and weaknesses of GBM drug discovery, emphasizing the trade-offs between effectiveness, toxicity, and specificity. It also provides insights for optimizing targeting based on compound structure and characteristics, targets, and putative toxicity through cheminformatic or experimental approaches.
    Conclusions: The GBMdrug1000 dataset is a public state-of-the-art resource for drug discovery and cheminformatics analysis, complemented by patent information and links to clinical trial data. This curated resource forms a framework for future prioritization of targets or their combinations.
    Keywords:  CRISPR-Cas9; clinical trials; glioblastoma drug dataset; patents; transcriptomics
    DOI:  https://doi.org/10.1093/noajnl/vdag030
  7. Nat Commun. 2026 Feb 28.
    Targeting leucine-rich repeat kinase 2 overcomes resistance to oncolytic herpes simplex virus-based therapies in glioblastoma.
    Yaning Qin, Zhiqi Liang, Mengqin Yu, Nanqian Lin, Naizhen Wang, Xuanke Huang, Shi Chen, Qun Peng, Yanhua Lin, Heqin Wang, Yipeng Rao, Zilong Xu, Shenghua Huang, Jingjing Cai, Yukui Li, Jun Zhang, Chaolong Lin, Guowei Tan, Ningshao Xia, Chenghao Huang.
      Glioblastoma (GBM) is an incurable brain tumor characterized by high heterogeneity. Oncolytic viruses (OVs) are an approved therapy, but their efficacy is often limited by poor cellular permissiveness to infection. Here we screen bioactive compounds to identify enhancers of oncolytic herpes simplex virus (oHSV) in GBM and discover a brain-penetrant leucine-rich repeat kinase 2 (LRRK2) inhibitor as the strongest sensitizer. Pharmacological LRRK2 inhibition potentiates oHSV infection and oncolysis across diverse GBM cell lines and improves therapeutic outcomes in patient-derived xenograft and orthotopic models. Mechanistically, LRRK2 interacts with and promotes STAT1 phosphorylation at Y701, which drives interferon-independent antiviral responses. Consequently, LRRK2 inhibition attenuates these host defenses, thereby enhancing tumor-selective viral replication. Elevated LRRK2 levels in GBM correlate with reduced oHSV sensitivity, suggesting LRRK2 as a predictive biomarker for tumors amenable to oHSV therapy. Our findings support the combination of LRRK2 inhibitors with oHSV as a promising therapeutic strategy for aggressive GBM.
    DOI:  https://doi.org/10.1038/s41467-026-70132-9
  8. Commun Biol. 2026 Mar 03.
    Downfield magnetic resonance signals serve as endogenous imaging biomarkers of nucleotide metabolism in glioma.
    Xinyi Zhu, Ke Zhou, Yang Cao, Jiaqiang Zhou, Yingchao Liu, Yibo Liu, Sheng Chen, Min Wang.
      Gliomas, the most common primary brain tumors, exhibit profound metabolic alterations that can be non-invasively probed using magnetic resonance spectroscopy (MRS). Compared to upfield signals in traditional MRS, downfield signals exhibit complex composition with limited understanding of their metabolite origins. Correlating high-throughput metabolic profiles provided by untargeted metabolomics with MRS signals can help elucidate the origins of metabolites in MRS. In this study, upfield and downfield MRS spectra are obtained from control and glioma-bearing male Wistar rats, followed by correlation analysis with untargeted metabolomics from corresponding brain tissues. Here, we show that multiple downfield MRS peaks are significantly elevated in glioma rats and correlate with metabolomic features. Notably, downfield MRS demonstrate the capability of capturing adenosine triphosphate (ATP)-associated nucleotide metabolism. Furthermore, MRS signatures exhibit predictive potential for tumor growth parameters. This work establishes an integrated MRS-metabolomics framework, providing a basis for non-invasively monitoring dynamic metabolic reprogramming and predicting glioma progression.
    DOI:  https://doi.org/10.1038/s42003-026-09780-y
  9. Nat Commun. 2026 Mar 03. pii: 2162. [Epub ahead of print]17(1):
    Contrast-free identification of glioma blood-brain barrier status via generative diffusion AI and non-contrast MRI.
    Kaiyi Zheng, Yiwen Zhang, Hai Shu, Ruolin Xiao, Xinming Li, Jianhua Ma, Qianjin Feng, Yuankui Wu, Wei Yang, Liming Zhong.
      Non-contrast MRI, routinely used for the preoperative diagnosis of glioma tumors and establishing treatment strategies, provides the potential for assessing blood-brain barrier (BBB) status without using gadolinium-based contrast agents (GBCA) which could cause adverse events. Additionally, generative artificial intelligence (AI) models enable the synthesis of contrast-enhanced images from non-contrast images. Despite this potential, the heterogeneity of GBCA-induced features in tumor areas and error accumulation from inaccurate synthesis largely limit the efficacy of conventional generative models. To address these limitations, we introduce a contrast-free BBB status identification model (CBSI) that can identify BBB status with high accuracy using non-contrast MR images and generative diffusion AI networks. Trained and validated on a multi-center dataset of 1,535 patients, CBSI achieves an area under the curve (AUC) of 81.31%, surpassing the performance of the model using only non-contrast MR (AUC = 72.76%) and demonstrating comparable performance to the T1Gd MR model (AUC = 88.68%) in an external test set. Furthermore, validation on two public datasets (BraTS-Africa and BraTS-GLI) supports the generalizability of CBSI in BBB status identification. Notably, with accurate BBB status of synthetic T1Gd, the performance of glioma segmentation and grading is improved significantly compared to existing methods. Generalizability analysis indicates that CBSI can facilitate BBB status identification using synthetic T1Gd findings, avoiding GBCA adverse effects and streamlining clinical workflows.
    DOI:  https://doi.org/10.1038/s41467-026-69578-8
  10. Commun Biol. 2026 Mar 05.
    Nucleoli-localized KANSL2 as an epigenetic regulator of ribosome biogenesis in glioblastoma cells.
    Nicolás Budnik, Lucía Canedo, Agustín E Morellato, Marina B Cuenca, Martina Garmendia, Sergio Senin, Sebastián A Romano, Zdenek Andrysik, Guillermo A Videla-Richardson, Michael W Graner, Ken Kobayashi, Yilong Zhou, Meike Wiese, Asifa Akhtar, Joaquín M Espinosa, Carolina Perez-Castro.
      KANSL2 is a subunit of the non-specific lethal (NSL) chromatin-modifying complex associated with glioblastoma (GBM) progression, but the intrinsic role of KANSL2 in GBM cells is poorly understood. By analyzing TCGA-GBM and GTEx datasets, we found that KANSL2 is upregulated in GBM and positively correlates with genes involved in ribosome biogenesis. Immunofluorescence and cell cycle analyses reveal a dynamic nuclear distribution, with KANSL2 becoming enriched in nucleoli mainly during G1/early S and G2 phases. Overexpression of KANSL2 increases 45S pre-rRNA and 28S rRNA levels, whereas its silencing reduces rRNA expression and histone H4 acetylation at lysines 5 and 8 within rDNA promoters. RNA-seq of patient-derived GBM spheroids confirms a global downregulation of ribosome biogenesis genes upon silencing of KANSL2. Together, these findings identify KANSL2 as a nuclear factor that transiently associates with nucleoli to promote rRNA transcription and ribosome biogenesis, supporting the biosynthetic and proliferative capacity of glioblastoma cells.
    DOI:  https://doi.org/10.1038/s42003-026-09808-3
  11. Cell Rep. 2026 Mar 04. pii: S2211-1247(26)00124-5. [Epub ahead of print]45(3): 117046
    Functionally distinct ALK and ROS1 fusions detected in infant-type hemispheric gliomas converge on STAT3 and SHP2 activation.
    Andreas Postlmayr, Astrid Sanchez Bergman, Jacob Torrejon Diaz, Bernard Ciraulo, Shen Yan, Nina Hofmann, Samanta Carbajal, Rosalie Dobler, Charbel Machaalani, Marc T Schönholzer, Laura Priego Gonzalez, Andrea J De Micheli, Ernesto Berenjeno-Correa, Luca Baroncini, Michael A Grotzer, Uri Tabori, Cynthia Hawkins, Olivier Ayrault, Marc Zuckermann, Martin Baumgartner, Ana S Guerreiro Stücklin.
      ALK and ROS1 fusions are key drivers of infant-type hemispheric gliomas (IHG). With diverse gene partners, the impact of ALK and ROS1 oncoprotein heterogeneity on glioma biology remains unknown. We developed an integrative phospho-proteomic and transcriptomic approach to discover biological functions regulated by five IHG-associated fusions: CCDC88A::ALK, PPP1CB::ALK, GOPC::ROS1, CLIP1::ROS1, and KIF21A::ROS1. Here, we report fusion-specific oncogenic functions conferred by the 5' gene partner, including increased cell motility driven by microtubule-interacting fusions CCDC88A::ALK and CLIP1::ROS1. All studied fusions converge on STAT3 activation. Using affinity purification mass spectrometry, we identified SHP2 in direct interaction with all three ROS1 oncoproteins but with none of the ALK oncoproteins, which in turn interact with SHC1/SHC3. ROS1 fusions phosphorylate SHP2 to a greater extent than ALK fusions, and analyses of downstream pathways suggest MAPK-independent, non-canonical SHP2-driven functions. Our findings reveal both common and fusion-specific dependencies, offering opportunities to optimize therapeutic strategies for pediatric gliomas.
    Keywords:  ALK; CP: cancer; ROS1; STAT3; brain tumors; cell motility; cell signaling; gene fusions; infant-type hemispheric gliomas; pediatric gliomas; receptor tyrosine kinases
    DOI:  https://doi.org/10.1016/j.celrep.2026.117046
  12. Oncogene. 2026 Mar 02.
    The multifunctional RNA helicase DDX39A drives glioblastoma progression by modulating WISP1 alternative splicing that induces an immunosuppressive macrophage polarization.
    Yan Zhang, Zhiwei Xue, Naibin Zhang, Yuehua Zhu, YanZhao Wu, Meilin Lv, Zhihan Zhang, Feiyu Mu, Wenchen Xing, Ziyi Tang, Chunjie Wang, Zhiyi Xue, Wenjing Zhou, Xiaofei Liu, Xingang Li, Rolf Bjerkvig, Bin Huang, Mingzhi Han, Jian Wang, Donghai Wang.
      Glioblastoma (GB) is a highly complex ecosystem characterized by numerous interactions between tumor cells and the surrounding tumor microenvironment (TME). Splicing factors play a pivotal role in processing nascent pre-mRNA and are important in the progression of cancer, making them promising molecular targets. In this study, we demonstrate that the DEAD-box helicase 39 A (DDX39A), a RNA helicase with several important roles in RNA metabolism and cellular processes, is significantly upregulated in GB and is primarily expressed in tumor cells, leading to an immunosuppressive macrophage polarization. Through in vitro and in vivo studies, we demonstrate that reducing DDX39A expression in GB results in reduced tumor growth and invasion. Mechanistically, through RNA-seq and RIP-seq, we identified WISP1 as a critical downstream effector of DDX39A. DDX39A stabilizes WISP1 pre-mRNA through alternative splicing regulation, thereby activating the AKT signaling pathway. We further demonstrate that WISP1, when secreted by tumor cells, functions as a paracrine signaling molecule that promotes the development of immunosuppressive tumor-associated macrophages (TAMs). Additionally, we demonstrate that Fluphenazine hydrochloride binds to and inhibits DDX39A, thereby suppressing GB growth, invasion, and the immunosuppressive function of macrophages. DDX39A thus represents a potential candidate for glioma-targeted therapy.
    DOI:  https://doi.org/10.1038/s41388-026-03715-x
  13. Neuro Oncol. 2026 Feb 05. pii: noag026. [Epub ahead of print]
    Spatial Transcriptomics Characterisation of Radionecrotic Changes in Glioblastoma Patients.
    Zaira Seferbekova, Michael Ritter, Gleb Ruckhovich, Sophia Schinkewitsch, Nela Köberer, Niklas Grassl, Maximilian Y Deng, Arne M Ruder, Laila König, Jürgen Debus, Uta Hanning, Frank A Giordano, Tobias Kessler, Violaine Goidts, Miriam Ratliff, Christel Herold-Mende, Sandro M Krieg, Nima Etminan, Michael Platten, Wolfgang Wick, David Reuss, Andreas Von Deimling, Felix Sahm, Moritz Gerstung, Abigail K Suwala.
       BACKGROUND: IDH-wildtype Glioblastoma (GB) is the most prevalent primary malignant CNS tumour in adults. The standard treatment regimen involves radiotherapy, which can cause radionecrotic (postactinic) changes as a late-onset treatment complication. While radiation is thought to mainly affect resident brain tissue, progressive GB and radionecrotic changes can be challenging to differentiate, as they may present with similar symptoms and appear alike on MRI. Therefore, histopathological examination remains the gold standard of diagnostics.
    METHODS: The cohort comprised ten samples from nine patients diagnosed with GB, all of whom underwent first-line standard of care treatment including surgery, radio- and chemotherapy with temozolomide. Subsequent radiological examination identified tumour progression in all patients, thus necessitating a second surgery. Following histopathological examination of the material collected from the second surgery, four patients were histologically diagnosed with tumour recurrence, four exhibited no evidence of recurrence but manifested with radionecrotic changes, and one patient demonstrated both. The spatial single cell transcriptomic profiling of the samples was conducted using the Xenium platform.
    RESULTS: We generated a comprehensive spatial single cell transcriptomic atlas of progressive GB and brain tissue with radionecrotic changes. Tumour cells were detected in samples from both groups. The employment of the dataset revealed that progressive GB samples contained OPC/NPC-like and proliferating tumour cells with high EGFR expression. Conversely, in samples with radionecrotic changes, tumour cells downregulated their EGFR expression even in the presence of gene amplification and did not show proliferation markers. Additionally, border-associated macrophages infiltrated the tissue and might have promoted gliosis in samples with radionecrotic changes.
    CONCLUSIONS: This study delineates a complex spatial architecture of brain tissue with post-treatment changes and its discrepancies from progressive GB, thus facilitating future research into novel treatment strategies.
    Keywords:  glioblastoma; necrosis; radiation; recurrence; spatial single cell transcriptomics
    DOI:  https://doi.org/10.1093/neuonc/noag026
  14. Oncogene. 2026 Mar 04.
    GITR activation potentiates anti-tumor immunity of tumor-infiltrating lymphocytes expanded from glioblastoma by rescuing exhaustion.
    Jiayi Zhou, Yinggui Yang, Ran Ye, Jiani Lin, Huiyi Feng, Xiaojuan Pei, Mingzhen Li, Jiangfan Peng, Xinzhi Yang, Peter Yat Ming Woo, Danny Tat Ming Chan, Penghui Zhou, Jie Mao, Zhuohao Liu, Dinglan Wu.
      Autologous tumor-infiltrating lymphocyte (TIL) therapy holds transformative potential for solid tumors, yet its efficacy in glioblastoma remains limited by T cell exhaustion and immunosuppression. In the current study, we optimized an effective and reliable method for in vitro expansion of TILs from glioblastoma lesions and assessed their tumor-killing capacity both in vitro and in vivo. Single-cell RNA sequencing (scRNA-seq) of expanded TILs uncovered their heterogeneity and identified a cytotoxic tissue-resident memory (TRM) CD8+ TIL subset with a unique exhaustion signature. Notably, the co-stimulatory factor GITR (encoded by TNFRSF18) is highly expressed not only on immunosuppressive regulatory T (Treg) cells but also on exhausted CD8+ TILs. GITR agonism via αGITR antibody achieved dual effects: it directly enhanced CD8+ TIL activation while simultaneously abrogating Treg-mediated immunosuppression. This dual-action mechanism synergized with αPD-1 therapy to amplify TIL reactivation, significantly enhancing tumor control in vivo. Mechanistically, GITR activation potentiated anti-tumor responses by promoting immunological synapse (IS) formation and function in TILs via the NF-κB/KALRN signaling axis. Our findings established GITR as a crucial regulator of CD8+ TIL anti-tumor immunity, positioning GITR targeting as a novel strategy to improve TIL therapy for glioblastoma, with promising implications for clinical application.
    DOI:  https://doi.org/10.1038/s41388-026-03705-z
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