bims-malgli 2026-02-08 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2026–02–08
sixteen papers selected by
Oltea Sampetrean, Keio University

Deciphering the tumor microenvironment and role of immunotherapy in Diffuse Midline Glioma: a scoping review.
3D heterotypic models of glioblastoma reveal the impact of microglia on cellular organization and the production of a distinct secretome.
Breaking down glioma primary cilia disassembly.
MIF-mediated reprogramming of myeloid lineage within the glioma tumor microenvironment impacts the efficacy of immune stimulatory gene therapy.
SAGA/ATAC complexes sustain aberrant chromatin regulation and promote tumorigenesis in diffuse midline glioma.
Beyond base camp: PI3K/mTOR inhibition for the treatment of pediatric high-grade gliomas.
lncRNA LUCAT1 Regulates DNA Damage Response in Glioma Stem Cells Under Hypoxia.
Meningeal blood vessel blockage enhances anti-glioblastoma immunity.
Preclinical efficacy of combinatorial B7-H3 CAR T cells and ONC206 against diffuse intrinsic pontine glioma.
Gut Microbiome Strategies for Enhancing ICI Delivery Across the BBB in Glioblastoma.
A genomically-tailored multi-agent precision medicine clinical trial for adults with recurrent glioblastoma.
Distinct tumor immune microenvironmental (TIME) landscapes drive divergent immunotherapy responses in glioblastoma.
Reduced expression of BIRC2 and BIRC3 associated with longer survival in pediatric high-grade gliomas.
Neural stem cells and glioblastoma stem cells: redefining concepts.
Classification accuracy of a hierarchical molecular inference-based deep-learning system for CNS tumour diagnosis: a multi-institutional, retrospective study.
Consideration of spatial companion biomarkers for targeted therapeutics in cancer: depatuxizumab mafodotin in glioblastoma.

Neuro Oncol. 2026 Feb 02. pii: noag014. [Epub ahead of print]

Deciphering the tumor microenvironment and role of immunotherapy in Diffuse Midline Glioma: a scoping review.

Christian K Ramsoomair, Felipe Sarmiento, Deryn Ramsoomair, Manav Daftari, Jiasen He, Benjamin Glazer, Michelle Monje, Danny Reinberg, Ashish H Shah.

  Diffuse midline glioma, H3 K27-altered, formerly known as diffuse intrinsic pontine glioma, (DIPG/DMG) is the most aggressive form of pediatric brain malignancy, with <10% 2-year overall survival after standard of care. The limited success of traditional immune checkpoint inhibitors in pediatric high-grade gliomas, including DMG, has highlighted the urgent need to re-examine the tumor's intrinsic and microenvironmental barriers to immunotherapy. Advances in molecular and spatial profiling have revealed the profound intratumoral heterogeneity, lineage plasticity, and complex immunosuppressive tumor microenvironment characteristic of DMG, which are shaped by diverse myeloid populations, neuronal integration, and spatially distinct tumor niches. These insights are informing the development of non-traditional immunotherapeutic approaches, including alternative checkpoint blockade, chimeric antigen receptor T cells, and viro-immunotherapy strategies, which aim to overcome DMG's unique immune escape mechanisms. We also outline key translational challenges and future directions necessary to accelerate progress, including the refinement of preclinical models, optimization of CNS-specific immunotherapy delivery, and the integration of patient-derived data into streamlined, collaborative clinical trial platforms.

Keywords:  Cancer neuroscience; Diffuse midline glioma (DMG); Immunotherapy; Pediatric brain tumors; Tumor microenvironment

DOI:  https://doi.org/10.1093/neuonc/noag014
Sci Rep. 2026 Feb 04.

3D heterotypic models of glioblastoma reveal the impact of microglia on cellular organization and the production of a distinct secretome.

Clara García-Sáez, Josune Alonso-Marañón, Mikel García-Puga, Ane Rubio-Zulaika, Irati de Goñi-Garcia, Lorea Blázquez, Sandra Camarero-Espinosa.

  Glioblastoma (GBM) is a deadly brain tumor with a very poor prognosis. Development of new therapeutics is hindered by the lack of appropriate preclinical models that reflect the complexity of the tumor microenvironment, especially the crucial role of microglia. In this study, we investigated the impact of microglia on GBM models using humanized 3D spheroids. Homotypic and heterotypic spheroids were created out of a GBM-derived cell line (DKMG) or patient-derived glioma stem cells (GB22-13), along with a microglia cell line (HMC3). Heterotypic glioma-HMC3 spheroids exhibited increased proliferation and greater drug resistance to chemotherapy drug Temozolomide compared with homotypic spheroids. Heterotypic spheroids also grew larger, developed multinucleated structures within 7 days, and had a greater invasive potential. Additionally, a distinct core-shell structure emerged in the heterotypic spheroids, with glioma cells concentrated in the core and a surrounding layer of microglia forming a protective shell that appeared to hinder drug penetration to the tumor core. Further, heterotypic cells were able to induce migration and polarization of peripheral blood monocytes (THP-1) towards M2 phenotypes, increasing immune evasion. These findings highlight the critical role of microglia in GBM development and progression, demonstrating their contribution to both reduced drug diffusion and increased tumor growth.

Keywords:  Glioblastoma; Malignancy; Microglia; Multicellular spheroids; Patient-derived cells; Spatial arrangement

DOI:  https://doi.org/10.1038/s41598-026-37395-0
Neurooncol Adv. 2025 Jan-Dec;7(1):7(1): vdaf217

Breaking down glioma primary cilia disassembly.

Matthew R Sarkisian, Loic P Deleyrolle, Joshua J Breunig.

  While many postmitotic cells in the body harbor cilia, certain aggressive cancers such as glioblastoma (GBM) display low frequencies of cells harboring a primary cilium. Ciliated GBM cells that plan to multiply have to disassemble their cilium in order for centrioles to duplicate and re-purpose for mitosis. Little is known about the molecular mechanisms underlying cilia disassembly in GBM, or whether this may represent a driving factor in disease onset, progression, or recurrence. In many cell types, ciliary disassembly is thought to be orchestrated by the aurora kinase A (AURKA) and histone deacetylase 6 (HDAC6) signaling axis. These molecules are often overexpressed in GBM, perhaps owing to the less frequent observation of ciliated GBM cells. Here, we review regulators of the core pathway, and discuss recent studies attempting to inhibit AURKA and HDAC6 in patient and mouse models of GBM and resulting effects on cilia. In the face of potent inhibitors, GBM cells appear to engage pathways independent of the core axis to promote cilia disassembly and/or engage other forms of modified axonemal tubulin to ensure persistence of cilia on GBM cells. GBMs upregulate a host of proteins implicated to drive cilia disassembly. Thus, clarifying these alternate mechanisms may be important as the roles of cilia in tumor formation and propagation, angiogenesis, and treatment resistance are increasingly reported. A deeper understanding of the role of cilia in these hallmarks of glioma may hold clues to the high recurrence rate of GBM.

Keywords:  AURKA; HDAC6; cancer stem cells; cilia; glioblastoma

DOI:  https://doi.org/10.1093/noajnl/vdaf217
bioRxiv. 2026 Jan 14. pii: 2026.01.13.699283. [Epub ahead of print]

MIF-mediated reprogramming of myeloid lineage within the glioma tumor microenvironment impacts the efficacy of immune stimulatory gene therapy.

Ziwen Zhu, Noah C Kanis, Anthony E George, Michael Albdewi, Yingxiang Li, Anzar A Mujeeb, Brandon L McClellan, Gurveer Singh, Jialin Liu, Wajd N Al-Holou, Jason A Heth, Joshua D Welch, Justin D Lathia, Pedro R Lowenstein, Richard Bucala, Maria G Castro.

Gliomas with mutant isocitrate dehydrogenase 1 (mIDH1) represent a distinct subgroup of brain tumors characterized by unique metabolic and immunological profiles compared to wildtype IDH1 (wtIDH1) gliomas. Despite recent progress, the cellular mechanisms underlying tumor progression and immune modulation in these subtypes remain poorly understood. In this study, we employed single-cell RNA sequencing (scRNA-seq) to characterize the cellular heterogeneity of wtIDH1 and mIDH1 gliomas, with a particular focus on myeloid cell populations. Our analyses revealed a marked reduction of monocyte-derived tumor-associated macrophages (Mo-TAMs) and lower expression of macrophage migration inhibitory factor (MIF) in mIDH1 gliomas, which was attributable to epigenetic reprogramming. Mechanistic studies using MIF and CD74 knockout mice demonstrated that the MIF-CD74 axis plays a crucial role in regulating the glioma immune microenvironment, thereby driving tumor growth and progression. Importantly, the combination of immune-stimulatory gene therapy (HSV1-thymidine kinase/Fms-like tyrosine kinase 3 ligand; TK/Flt3L) with MIF inhibition significantly extended survival in models of wtIDH1 glioma. These findings highlight the therapeutic potential of targeting the MIF-CD74 pathway and underscore the importance of integrating immunomodulatory strategies for the treatment of glioma.
Highlights: Mutant IDH1 gliomas exhibit fewer Mo-TAMs and increased Mg-TAMsMutant IDH1 gliomas have less MIF expression via epigenetic reprogramming.Mesenchymal wtIDH1 glioma cells are main source of MIF.MIF inhibition plus immune stimulatory gene therapy extends survival wtIDH1 glioma.

DOI: https://doi.org/10.64898/2026.01.13.699283
bioRxiv. 2026 Jan 23. pii: 2026.01.22.701194. [Epub ahead of print]

SAGA/ATAC complexes sustain aberrant chromatin regulation and promote tumorigenesis in diffuse midline glioma.

Rosemary U Richard, Caitlin Bagnetto, Rebecca L Murdaugh, Brittany R Eberl, Alan L Jiao, Adam F Kebede, Barry M Zee, Margaret M Harrington, Mariella G Filbin, Akdes Serin-Harmanci, Yang Shi, Jamie N Anastas.

Diffuse midline gliomas (DMG) are aggressive pediatric brain tumors characterized by chromatin and transcriptional dysregulation induced by H3K27M mutations. Strategies for overcoming epigenetic dysfunction to reduce DMG tumorigenesis remain limited. We identified multiple components of the SAGA and ATAC chromatin regulatory complexes as DMG genetic dependencies and found that genetic or pharmacological inhibition of the SAGA/ATAC-associated chromatin reader SGF29 reduces DMG proliferation. Small molecules targeting SAGA/ATAC-associated histone acetylation, ubiquitination, and methylation similarly suppressed DMG growth. Further chromatin profiling and RNAseq analyses reveal that SGF29 controls H3K9ac and H3K4me3 dynamics at both H3K27M-bound and H3K27M-independent target genes linked to proliferation, differentiation, and metabolism. Finally, we find that SAGA/ATAC inhibition may reduce DMG viability by repressing cholesterol metabolism gene expression and show that combinations of cholesterol- and SAGA/ATAC-targeting drugs synergistically reduce DMG growth. These findings reveal a functional link between SAGA/ATAC-dependent chromatin modulation and both transcriptional and metabolic dysregulation underlying DMG malignancy.

DOI: https://doi.org/10.64898/2026.01.22.701194
Neuro Oncol. 2025 Sep 11. pii: noaf163. [Epub ahead of print]

Beyond base camp: PI3K/mTOR inhibition for the treatment of pediatric high-grade gliomas.

Ryan J Duchatel, Clara Savary, Zacary P Germon, Madisen Riley, David S Ziegler, Sabine Mueller, Evangeline R Jackson, Matthew D Dun.

  Pediatric high-grade glioma (pHGG), including diffuse midline glioma (DMG), are the most aggressive and fatal pediatric cancers. Mutations and amplifications within the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway drive tumor growth, treatment resistance, and poor outcomes. Although PI3K and mTOR have been identified as genetic dependencies in pHGGs, translating this knowledge into effective treatment remains challenging. The blood-brain barrier (BBB) restricts the delivery of most PI3K/mTOR inhibitors and , hence, often show poor CNS penetration. Even when present in the brain, these agents frequently encounter adaptive resistance mechanisms that blunt efficacy. Side effects, including hyperglycemia, rash, and mucositis, further complicate their use and reduce compliance. Encouragingly, novel brain-penetrant PI3K/mTOR inhibitors offer new opportunities for treatment, but combining these agents with other therapies, including chemotherapy, other small molecules, and immunotherapies, requires careful balancing of toxicity and efficacy. Therefore, achieving optimal dosing for each patient remains a significant hurdle. This review examines the promise and pitfalls of targeting the PI3K/mTOR pathway in DMG, including the limitations of available therapies, mechanisms of resistance, and the critical need for improved regimen design. We propose a roadmap to guide future efforts, emphasizing rational combination strategies and better patient stratification to improve survival for children diagnosed with these devastating cancers.

Keywords:  PI3K; clinical trials; diffuse midline glioma; high-grade glioma; mTOR

DOI:  https://doi.org/10.1093/neuonc/noaf163
Neuro Oncol. 2026 Jan 31. pii: noag017. [Epub ahead of print]

lncRNA LUCAT1 Regulates DNA Damage Response in Glioma Stem Cells Under Hypoxia.

Haidong Huang, Hariti Shah, Himanshu Dashora, Molly Guthrie, Lilah Maclowry, Zhi Huang, Dalya Khalife, Jianhong Lin, Shideng Bao, Richard Prayson, Liangqi Xie, Jianjun Zhao, Jennifer S Yu.

   BACKGROUND: Genomic stability is essential for cell survival, particularly under stress conditions like hypoxia, which disrupt DNA repair. Glioblastoma (GBM) is markedly resistant to DNA-damaging therapies, primarily due to glioma stem cells (GSCs) and the hypoxic tumor microenvironment. Long non-coding RNAs (lncRNAs) play a significant role in maintaining genome integrity, but their involvement in the DNA damage response (DDR) under hypoxic conditions in GSCs remains unclear. We previously identified LUCAT1 as the most highly induced lncRNA in GSCs under hypoxia and a key regulator HIF1α activity. We now investigate its role in DDR regulation.
METHODS: LUCAT1-interacting proteins in GSCs under hypoxia were identified using identification of direct RNA interacting proteins (iDRIP) and mass spectrometry. Interactions were confirmed by RNA pulldown and RNA immunoprecipitation. Mechanistic studies involved immunoprecipitation, proximity ligation assays, comet assays, immunostaining, and LUCAT1 knockdown using shRNA. Gene expression changes were evaluated via RNAseq in GSCs and TCGA datasets. Functional assays were conducted in GSCs and orthotopic xenografts with LUCAT1 depletion alone or in combination with PARP or DNA-PK inhibition or radiation.
RESULTS: LUCAT1 directly interacts with the DNA-PK holoenzyme, modulating its assembly and function in the non-homologous end joining (NHEJ) pathway. It also regulates BRCA1 and RAD51, key proteins in homologous recombination (HR). Depletion of LUCAT1 increased DNA damage, sensitized GSCs to DDR inhibitors, and improved survival in mice treated with radiotherapy.
CONCLUSIONS: LUCAT1 is a critical DDR regulator in GSCs under hypoxia and a promising target to enhance the efficacy of DDR inhibitors and radiotherapy in GBM.

Keywords:  DNA damage repair; glioblastoma; glioma stem cells; hypoxia; lncRNA

DOI:  https://doi.org/10.1093/neuonc/noag017
Cell. 2026 Feb 04. pii: S0092-8674(25)01494-1. [Epub ahead of print]

Meningeal blood vessel blockage enhances anti-glioblastoma immunity.

Yixin Gao, Yushan Peng, Jiying Cheng, Xinyu Zhang, Jian Zhong, Chenfei Lu, Xudong Xing, Yanxing Lai, Huixin Sun, Xuechao Zeng, Zhiying Liu, Kejun He, Xinman Liu, Feizhe Xiao, Xiuxing Wang, Fan Bai, Nu Zhang.

  The dura mater, the outermost meningeal layer that samples and presents central nervous system (CNS)-derived antigens, is a pivotal interface for CNS immunosurveillance. Here, we show that meningeal blood vessel blockage effectively suppresses glioblastoma (GBM) progression in murine models. Single-cell profiling of dura reveals a resident border-associated macrophage (rBAM) subset characterized by high neonatal Fc receptor expression, which endows rBAMs with superior capacity for presenting tumor antigens and activating CNS-patrolling T cells. Meningeal blood vessel blockage preserves dural cerebrospinal fluid (CSF)-1 levels by restricting circulation-derived BAM (cBAM) and expands the rBAM pool, thereby enhancing T cell activation at the dura interface and amplifying intratumoral cytotoxic T cell responses. Clinically, rBAM abundance positively correlates with GBM patient survival. Our findings show that the dura is a critical regulator of anti-tumor immunity in CNS cancers and propose that meningeal blood vessel blockage may be a surgical strategy to potentiate GBM immunotherapy.

Keywords:  antitumor T cell; border-associated macrophage; glioblastoma; meningeal blood vessel blockage; meningeal immunity; tumor microenvironment

DOI:  https://doi.org/10.1016/j.cell.2025.12.045
Neuro Oncol. 2026 Feb 04. pii: noag025. [Epub ahead of print]

Preclinical efficacy of combinatorial B7-H3 CAR T cells and ONC206 against diffuse intrinsic pontine glioma.

Andrea Timpanaro, Edward Z Song, Ryma Toumi, Leonel Elena-Sanchez, Caroline Piccand, Kelsey Nemec, Anja Kordowski, Davina Lau, Scott Johnson, Lily Winter, Ashmitha Rajendran, Rebecca Ronsley, Shannon K Oda, Joshua Gustafson, Jason P Wendler, Carl Koschmann, Myron Evans, Siobhan Pattwell, Michael C Jensen, Jessica B Foster, Matthew D Dun, Michael Meechan, Matthew C Biery, Nicholas A Vitanza.

   BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric brain tumor affecting over 300 children annually in the United States. Chimeric antigen receptor (CAR) T cells are a targeted immune effector cell therapy with substantial clinical benefit against hematologic cancers. Against CNS tumors, CAR T cells targeting B7-H3, a protein highly expressed on DIPG, have rapidly advanced from preclinical studies to clinical trials. BrainChild-03 (NCT04185038), a phase 1 trial of repeatedly delivered intracerebroventricular (ICV) B7-H3-targeting CAR T cells (B7-H3 CAR T cells), demonstrated tolerability and potential efficacy for children and young adults with DIPG. However, clinical benefits were not uniformly seen, and multi-agent treatment strategies may be required against such an aggressive disease. Here, we combined B7-H3 CAR T cells with ONC206, an imipridone molecule also under clinical investigation.
METHODS: We tested B7-H3 CAR T cells combined with ONC206 across multiple DIPG cell cultures and orthotopic xenograft mouse models.
RESULTS: B7-H3 CAR T cell monotherapy induced robust cytotoxicity while ONC206 treatment resulted in significant mitochondrial dysfunction against DIPG cells. The combination of low effector-to-target ratios of B7-H3 CAR T cells and IC50 concentrations of ONC206 led to significantly enhanced cytotoxicity in vitro (p < 0.003) and increased IL-2, IL-29, VEGF-A, and Granzyme B levels. In vivo combinatorial studies of ONC206 and a single ICV dose of B7-H3 CAR T cells extended survival in DIPG xenograft mouse models.
CONCLUSIONS: B7-H3 CAR T cells combined with ONC206 is a feasible and efficacious multi-agent approach against multiple DIPG models.

Keywords:  B7-H3; CAR T cell therapy; H3K27-altered (DMG); ONC206; diffuse intrinsic pontine glioma (DIPG); diffuse midline glioma

DOI:  https://doi.org/10.1093/neuonc/noag025
Biofactors. 2026 Jan-Feb;52(1):52(1): e70077

Gut Microbiome Strategies for Enhancing ICI Delivery Across the BBB in Glioblastoma.

Sama Barati, Sahar Ghoflchi, Ali Nakhaei, Mahla Palizkaran Yazdi, Pejman Hosseinzadeh, Hossein Hosseini, Mohammad Jalili-Nik.

  Glioblastoma (GB) is highly malignant with a median survival of 14 months despite conventional treatments like surgery, radiotherapy, and temozolomide. Resistance to these therapies necessitates innovative approaches, such as immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death ligand 1 (PD-L1) to enhance T-cell-mediated tumor destruction. However, clinical trials have shown limited ICI efficacy in GB due to its immunosuppressive microenvironment and the blood-brain tumor barrier (BBTB), which impairs drug delivery. Emerging evidence highlights the gut microbiota as a pivotal modulator of ICI response, enhancing CD8+ and CD4+ T-cell function, antigen presentation, and immune modulation via the gut-brain axis in cancers. In addition, studies showed that gut-derived metabolites, including short-chain fatty acids, modulate immune responses and support blood-brain barrier integrity by regulating inflammatory signaling and tight junction proteins. Future GB research should prioritize clinical trials, mechanistic studies, and interventional strategies like fecal microbiota transplantation and probiotics to enhance ICI efficacy.

Keywords:  blood–brain barrier; glioblastoma; gut microbiome; immune cell; immune checkpoint inhibitors

DOI:  https://doi.org/10.1002/biof.70077
Clin Cancer Res. 2026 Feb 06.

A genomically-tailored multi-agent precision medicine clinical trial for adults with recurrent glioblastoma.

Jiaying Chen, Nancy Ann Oberheim Bush, Jennifer A Grabowsky, Cassie Kline, Deanna L Kroetz, Jennie W Taylor, Javier Villanueva-Meyer, Annette M Molinaro, John F de Groot, Nicholas A Butowski, Meghan Tedesco, Jane Rabbitt, Joanna J Phillips, Shawn Hervey-Jumper, Manish K Aghi, Mitchel S Berger, Edward F Chang, Susan M Chang, David A Solomon, Jennifer L Clarke.

PURPOSE: Existing salvage therapies for recurrent glioblastoma (rGBM) have limited efficacy, with median survival of approximately 9 months. Given the complex molecular heterogeneity of GBM, single-target approaches have consistently failed as a treatment strategy. We conducted a phase 1 clinical trial to assess the feasibility, safety, and efficacy of a genomically-tailored multi-agent regimen in 30 adults with surgically-treated rGBM.
PATIENTS AND METHODS: Adults with IDH-wildtype glioblastoma (n=29) or grade 4 IDH-mutant astrocytoma (n=1) were consented and underwent clinically-indicated surgery for recurrent disease. Comprehensive genomic profiling was performed on the recurrent tumors, and results for each patient were discussed at an individualized molecular tumor board to determine a personalized treatment regimen combining up to 4 FDA-approved drugs, including one cytotoxic agent as backbone.
RESULTS: A total of 12 drugs were used in 18 combinations - the most common regimen was lomustine, afatinib, and abemaciclib (n=8). The most common toxicities included cytopenias, rash, and gastrointestinal symptoms, requiring frequent dose reductions. Measured from surgery at trial enrollment, progression-free survival at 6 months (PFS-6) was 40%, overall survival at 9 months (OS-9) was 73%, and median OS was 12.7 months. After trial therapy, genomic profiling performed on subsequent recurrent tumor specimens identified genetic evolution corresponding to putative treatment resistance mechanisms.
CONCLUSIONS: Implementation of individualized treatment regimens in a timely fashion was feasible for patients with surgically resectable rGBM. Overall efficacy was not significantly improved compared to a contemporary patient cohort treated without experimental regimens, with full dosing of most combination therapies limited by toxicities.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-4080
Neuro Oncol. 2026 Jan 31. pii: noag018. [Epub ahead of print]

Distinct tumor immune microenvironmental (TIME) landscapes drive divergent immunotherapy responses in glioblastoma.

Linqian Weng, Krish Skandha Gopalan, Mélanie Guyot, Maxime Vanmechelen, Pouya Nazari, Marie Duhamel, Clelia Donisi, Carla Pallarés-Moratalla, Abhishek D Garg, Kieron White, Annette T Byrne, Diether Lambrechts, Frederik De Smet, Gabriele Bergers.

   BACKGROUND: Immunotherapies have improved outcomes in many cancers but remain largely ineffective in glioblastoma (GBM). We investigated whether immunotherapy could be rationally tailored to GBM by functionally subtyping the tumor immune microenvironment (TIME) and associated vascular landscapes.
METHODS: Single-cell and single-nucleus RNA sequencing, multiplex immunohistochemistry and flow cytometry were used to define TIME subtypes in human and murine GBMs. Therapeutic responses to anti-angiogenic and immunomodulatory therapies, including CD40 agonism, anti-PDL1, and PI3Kγ/δ inhibition, were assessed in orthotopic syngeneic GBM mouse models.
RESULTS: Three distinct functional TIME subtypes with unique vascular-immune landscapes were identified in human and murine GBM. TIME-low tumors were immune-low/deserted with a leaky vasculature. TIME-med GBM exhibited intermediate immune-infiltration, prominent angiogenesis and active immune responses. TIME-high tumors showed dense infiltration of immunosuppressive myeloid cells and dysfunctional T cells. Representative mouse models demonstrated subtype-specific sensitivities to anti-angiogenic immunomodulating therapies. TIME-low GBMs exhibited transient T-cell activation but relapsed due to myeloid-driven immunosuppression and mesenchymal transition. TIME-med tumors displayed the most favorable responses across anti-angiogenic immunomodulating therapies. TIME-high GBMs were largely resistant, although therapeutic efficacy improved with myeloid-targeted PI3Kγ inhibition. In contrast, CD40 agonist therapy worsened survival by enhancing angiogenesis, amplifying immunosuppression, impairing T cell function, reducing NK-cell recruitment, and promoting tumor propagation.
CONCLUSIONS: GBM comprise three functional TIME subtypes with divergent vascular-immune landscapes that require subtype-specific therapeutic strategies. TIME-med tumors are most amenable to immunotherapies. TIME-low tumors derive transient effects with anti-angiogenic immunomodulating therapies, and TIME-high are resistant or even experience worse outcome without targeted reversal of myeloid immunosuppression.

Keywords:  Anti-angiogenic therapy; Glioblastoma; Immunotherapy; Single-cell RNA sequencing; Tumor immune microenvironment (TIME) subtypes

DOI:  https://doi.org/10.1093/neuonc/noag018
Sci Rep. 2026 Jan 30.

Reduced expression of BIRC2 and BIRC3 associated with longer survival in pediatric high-grade gliomas.

Alicja Petniak, Paulina Gil-Kulik, Julia Zarychta, Adrian Kowalczyk, Joanna Trubicka, Marta Perek-Polnik, Cezary Grochowski, Ryszard Maciejewski, Wiesława Grajkowska, Janusz Kocki.



Keywords:  BIRC; GFAP; IAP family; Ki67; Olig2; Pediatric high grade glioma; Synaptophysin; p53

DOI:  https://doi.org/10.1038/s41598-026-35887-7
Crit Rev Oncol Hematol. 2026 Feb 04. pii: S1040-8428(26)00074-0. [Epub ahead of print] 105187

Neural stem cells and glioblastoma stem cells: redefining concepts.

Víctor M Arce, Lara González-Rendo, Laura Porres-Ventín, Valentina González-Álvarez, Sabela Caamaño-Teixeira, Cristina Almengló, Rosa Señarís, José A Costoya.

  Stem cells (SCs) represent a distinctive population of undifferentiated cells with the extraordinary ability to self-renew and differentiate into multiple cell types. Owing to this, SCs play a crucial role in maintaining tissue homeostasis, providing a source for the replacement of cell losses due to normal wear and tear. In addition, SCs display an unquestioned therapeutic potential, which has resulted in the development of several cell therapies for the treatment of different types of diseases. However, despite their remarkable potential, the therapeutic use of SCs must still face several challenges, which include ethical, legal and technical issues. Ethical and legal concerns are mainly related to the use of SCs obtained from human embryos, while technical problems mostly arise from the difficulty of appropriately directing the differentiation of the SCs to meet the tissue´s needs and the occurrence of events such as immune rejections. In addition, the safety of SC-based therapies is also under debate. Although they may offer a useful and harmless treatment for many pathologies, including some incurable and/or life-threatening diseases, a potential risk of tumorigenicity may also exist in some cases. Accumulating evidence also implicates SCs as the origin of, at least, some types of cancer. This is the case of glioblastoma (GBM), the most prevalent glioma type in adults, whose origin has been related to postnatal neural stem cells (NSCs), mainly located in the subventricular zone (SVZ) and the dentate gyrus in the hippocampus. It has been proposed that these NSCs may give rise to glioblastoma stem cells (GSCs), which through complex interactions with the tumor microenvironment exert a crucial effect on tumor growth and development.

Keywords:  Cancer stem cells; Cellular reprogramming; Glioblastoma; Glioblastoma stem cells; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.critrevonc.2026.105187
Lancet Oncol. 2026 Feb;pii: S1470-2045(25)00661-8. [Epub ahead of print]27(2): 243-253

Classification accuracy of a hierarchical molecular inference-based deep-learning system for CNS tumour diagnosis: a multi-institutional, retrospective study.

H Lalchungnunga, Christopher H Dampier, Omkar Singh, Danh-Tai Hoang, Eldad D Shulman, Zied Abdullaev, Bochong Li, Zhirui Luo, Zhichao Wu, Thomas M Pearce, Daniel F Marker, Kathleen McCortney, Craig Horbinski, Calixto-Hope G Lucas, Patrick J Cimino, MacLean P Nasrallah, Martha Quezado, Hye-Jung Chung, Leeor Yefet, Gelareh Zadeh, Sebastian Brandner, Eytan Ruppin, Kenneth Aldape.

BACKGROUND: Recent advances in artificial intelligence (AI) and computer vision empower deep-learning models to infer molecular features from histopathological images to classify CNS tumours. The aim of this study was to test the classification accuracy of a molecular inference-based AI assistant for CNS tumour diagnosis.
METHODS: In this multi-institutional, retrospective study, we used data from whole slide images of samples from patients aged 0-95 years, diagnosed with primary or recurrent CNS tumours. Reference diagnostic labels were determined by DNA methylation-based tumour classification to match one of 52 tumour types selected to encompass most types of gliomas, embryonal tumours, and meningeal and mesenchymal tumours encountered in clinical practice. The Neuropath-AI model was trained on 5835 samples from the National Cancer Institute (NCI; USA), the Children's Brain Tumor Network (USA), and the Digital Brain Tumour Atlas (Austria) to infer molecular features from whole slide images and to use these to predict tumour types with associated confidence scores. The test cohort comprised 5516 samples identified in laboratory archives between May 17, 2024, and May 13, 2025, from the NCI, Northwestern Medicine (USA), University of Pittsburgh Medical Center (USA), and University College London (UK). There were 2753 (50%) female and 2763 (50%) male patients, median age 43 years (IQR 25-59). The primary objective was to measure the classification accuracy of the model family-level and terminal classification predictions in test samples, with coprimary endpoints of sample coverage and prediction and balanced accuracy. Sample coverage was defined as samples receiving a model prediction with a confidence score above a specified threshold. Prediction accuracy and balanced accuracy were analysed in the covered samples (ie, those meeting the confidence criterion) and evaluated by comparing the top-1 or top-2 predictions with reference labels.
FINDINGS: Family-level classifications were reached in 5299 (96%) of 5516 samples. Predictions to one of the terminal classifications with at least moderate confidence were reached for 4772 (87%) samples. The single highest-scoring classification matched the reference label in 3817 (95% CI 3770-3865; 80% [95% CI 79-81]) of 4772 samples (balanced accuracy 66% [95% CI 63-70]). The two highest-scoring classifications contained the reference label in 4103 (95% CI 4056-4152; 86% [95% CI 85-87]) of 4772 samples (balanced accuracy 75% [95% CI 71-78]).
INTERPRETATION: Our model provides the basis for a clinically applicable deep-learning assistant to improve human efficiency and accuracy of CNS tumour diagnosis. The model will be made publicly available and could be implemented to assist human pathologists in future prospective studies.
FUNDING: The Intramural Research Program of the National Institutes of Health.

DOI: https://doi.org/10.1016/S1470-2045(25)00661-8
JCI Insight. 2026 Feb 03. pii: e198475. [Epub ahead of print]

Consideration of spatial companion biomarkers for targeted therapeutics in cancer: depatuxizumab mafodotin in glioblastoma.

Rimas V Lukas, Ruochen Du, Harrshavasan Congivaram, Kathleen McCortney, Karan Dixit, Craig Horbinski, Margaret Schwartz, Raymond Lezon, Lauren Singer, Ditte Primdahl, Jigisha Thakkar, Amy B Heimberger, Roger Stupp, Priya Kumthekar.



Keywords:  Brain cancer; Neuroscience; Oncology

DOI:  https://doi.org/10.1172/jci.insight.198475