Advances in Glioblastoma: From Biology to Therapeutics

Topic Information

Dear Colleagues,

Glioblastoma is the most common malignant brain tumor. Despite all efforts to combat it, the average life expectancy after diagnosis is between 12 and 15 months. It is a very heterogeneous tumor at the cellular and molecular levels. Its complexity has led to it being classified according to the WHO repeatedly, first as primary—or de novo—and secondary glioblastoma, and subsequently as one of four molecular types of glioblastoma (proneural, classic, neural, and mesenchymal); finally, it is taken into account whether glioblastoma presents IDH mutations or not . Treatment with surgery, radiotherapy, and temozolomide—when the MGMT enzyme is not expressed—is what the clinic can offer today to patients with glioblastoma. This Topic accepts manuscripts that show advances in the knowledge of glioblastoma, from a biological, genetic, and pathological point of view, especially when such advances have a translational effect at the clinical level. A special mention must be made regarding brain tumor stem cells, since they are considered the initiators and maintainers of the tumor. They are highly tumorigenic and cause resistance to chemotherapy and radiotherapy, thus complicating the comprehensive treatment of this pathology. We also hope to publish articles on liquid biopsy, epigenetic etiology and treatments, studies in organoids, mesenchymal stem cells, and the role of artificial intelligence in pathology and neurosurgery. This Topic will include both original research articles and reviews.

Prof. Dr. Javier S. Castresana
Prof. Dr. Miguel Idoate
Topic Editors

Keywords

Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biomolecules biomolecules	5.6	9.3	2011	16.6 Days	CHF 2700
Cancers cancers	4.8	9.0	2009	17.5 Days	CHF 2900
Cells cells	6.0	11.4	2012	14.9 Days	CHF 2700
Current Oncology curroncol	3.6	6.1	1994	22.6 Days	CHF 2200
Organoids organoids	2.8	4.3	2022	26.3 Days	CHF 1200

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Published Papers (6 papers)

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All Biomolecules Cancers Cells Organoids Current Oncology

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Open AccessArticle

Metformin Suppresses Glioblastoma Tumor Growth and Progression Through the AMPK/FoxO3a/Survivin Axis

by Fabiola Cavaliere, Michele Pellegrino, Alessandro Cormace, Sofia Spadafora, Mariarosa Fava, Seung Ho Yang, Jung Eun Lee, Marta Claudia Nocito, Rosa Sirianni, Ivan Casaburi, Cecilia Garofalo, Diego Sisci, Catia Morelli and Marilena Lanzino

Cells 2026, 15(3), 310; https://doi.org/10.3390/cells15030310 - 6 Feb 2026

Cited by 1 | Viewed by 1886

Abstract

Glioblastoma (GB) is one of the most aggressive malignant brain tumors. Due to the high invasiveness of this cancer, surgical removal is often not possible, and relapses after surgery are very common, making current treatments ineffective. Developing new therapies or treatment combinations remains [...] Read more.

Glioblastoma (GB) is one of the most aggressive malignant brain tumors. Due to the high invasiveness of this cancer, surgical removal is often not possible, and relapses after surgery are very common, making current treatments ineffective. Developing new therapies or treatment combinations remains a major challenge in managing GB. Metformin (MET), an anti-diabetic medication, has recently gained attention for its potential anticancer effects. To better understand how MET inhibits GB growth at the molecular level, we studied its impact on survivin, a member of the inhibitor of apoptosis (IAP) family that is essential for GB cell survival, resistance to radio- and chemotherapy, and tumor recurrence. Using T98G and U87-MG cell lines, we performed cell viability, migration, and invasion assays, along with Western blot analysis, ChIP assays, and gene silencing experiments to examine key signaling pathways. We found that MET effectively inhibits the growth, viability, and invasiveness of GB cell lines through a molecular mechanism involving activation of the AMPK/FoxO3a/survivin pathway. In vivo studies support these findings, showing increased FoxO3a and decreased survivin in brain tissue sections from metformin-treated mice compared with untreated controls. These results suggest new possibilities for repurposing MET as an adjuvant treatment for GB. Full article

(This article belongs to the Topic Advances in Glioblastoma: From Biology to Therapeutics)

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20 pages, 10200 KB  

Open AccessArticle

Small Molecule Cocktail DLC79 Suppresses Gliomagenesis by Activating Ascl1 and Remodeling Transcriptome

by Chuxiao Mao, Zhancheng Deng, Zhuming Chen, Lirong Huang, Caiyun Wang, Gong Chen and Qingsong Wang

Cells 2026, 15(2), 211; https://doi.org/10.3390/cells15020211 - 22 Jan 2026

Viewed by 860

Abstract

Glioblastoma (GBM) remains incurable due to its invasive growth and therapeutic resistance. While the neurogenic transcription factor-mediated reprogramming of glioma cells has been reported, pharmacological reprogramming offers a promising alternative due to its potential advantages for clinical translation. Using phenotype-driven screening, we identified [...] Read more.

Glioblastoma (GBM) remains incurable due to its invasive growth and therapeutic resistance. While the neurogenic transcription factor-mediated reprogramming of glioma cells has been reported, pharmacological reprogramming offers a promising alternative due to its potential advantages for clinical translation. Using phenotype-driven screening, we identified a multi-target small-molecule cocktail DLC79 (DAPT, LDN193189, CHIR99021, I-BET762, and Isx9) that effectively reprograms human glioma cells into neuron-like cells by activating endogenous ASCL1 (174.4-fold) and remodeling the transcriptional landscape. This conversion led to the strong upregulation of neuronal markers (e.g., MAP2 and GAD67) and suppression of glial identity. Functionally, DLC79 treatment inhibited glioma malignancy in vitro, impairing proliferation, migration, invasion, and clonogenicity. In a subcutaneous xenograft model, brief pretreatment with DLC79 significantly attenuated the tumorigenic potential of glioma cells, reducing tumor bioluminescence by 56% and tumor mass by 47%. Our study establishes pharmacological reprogramming as a promising anti-glioma strategy that leverages neuronal conversion to reduce oncogenic properties, thereby initiating a novel therapeutic paradigm. Full article

(This article belongs to the Topic Advances in Glioblastoma: From Biology to Therapeutics)

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14 pages, 2562 KB  

Open AccessArticle

The Spatial Signature of Glioblastoma: A Statistical Re-Assessment of Anatomical Distribution Based on Methylation Subtypes

by Tim Herrmann, Claire Delbridge, Michael Griessmair, Julian Canisius, Meike Mitsdoerffer, Denise Bernhardt, Isabel C. Hostettler, Chiara Negwer, Igor Yakushev, Bernhard Meyer, Friederike Schmidt-Graf, Stephanie E. Combs, Jan S. Kirschke, Benedikt Wiestler and Marie-Christin Metz

Cells 2026, 15(2), 175; https://doi.org/10.3390/cells15020175 - 19 Jan 2026

Viewed by 1330

Abstract

Precise molecular characterization of glioblastoma (GB) is fundamental for accurate risk stratification and therapeutic planning. DNA methylation profiling reliably identifies key molecular features, including O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status and specific molecular subtypes, such as receptor tyrosine kinase (RTK) I and II, [...] Read more.

Precise molecular characterization of glioblastoma (GB) is fundamental for accurate risk stratification and therapeutic planning. DNA methylation profiling reliably identifies key molecular features, including O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status and specific molecular subtypes, such as receptor tyrosine kinase (RTK) I and II, and the mesenchymal (MES) subtype. In this study, we investigated the hypothesized correlation between these molecular profiles and preferential tumor locations, which could reveal a link to underlying tumor biology. We analyzed 227 GB patients characterized by DNA methylation profiling. To map significant clusters of tumor occurrence across subtypes and subcomponents, we performed voxel-wise analysis of differential involvement, utilizing 500 permutations to correct for multiple comparisons. While uncorrected frequency differential maps suggested localization tendencies for the RTK I, RTK II, and MES subtypes, stringent statistical correction revealed only one robust association: the non-enhancing component of MES tumors showed significant clustering in the left frontal lobe, the insula, and the temporal lobe. Contrary to prior literature, we observed no significant hemispheric preference regarding MGMT promoter methylation status. Our findings challenge prior assumptions regarding the spatial distinctiveness of GB subtypes and highlight the need to further elucidate the mechanisms governing tumorigenesis and spatial growth patterns. Full article

(This article belongs to the Topic Advances in Glioblastoma: From Biology to Therapeutics)

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27 pages, 1422 KB  

Open AccessReview

Combined Tumor Cell and Lysate-Based Vaccines for Immunotherapy of Primary and Recurrent Glioblastoma (GBM)

by Apostolos Stathopoulos, Philippe Glorieux, Evangelos M. Rokas and Huub F. J. Savelkoul

Cancers 2025, 17(23), 3772; https://doi.org/10.3390/cancers17233772 - 26 Nov 2025

Cited by 1 | Viewed by 2809

Abstract

Glioblastoma (GBM) remains the most aggressive primary brain tumor, characterized by extensive intra-tumoral heterogeneity, profound local immunosuppression, and a highly adaptive tumor microenvironment that resists conventional therapies. Immunotherapy for GBM tries to overcome these barriers by reactivating anti-tumor immunity through cellular, molecular, and [...] Read more.

Glioblastoma (GBM) remains the most aggressive primary brain tumor, characterized by extensive intra-tumoral heterogeneity, profound local immunosuppression, and a highly adaptive tumor microenvironment that resists conventional therapies. Immunotherapy for GBM tries to overcome these barriers by reactivating anti-tumor immunity through cellular, molecular, and immune-modulatory interventions. The therapeutic efficacy of the cell-based vaccines in patients with glioma and glioblastoma is primarily driven by tumor antigen-specific CD8⁺ T cell activation, orchestrated by CD4⁺ T cell help. Several whole-cell vaccine platforms (e.g., DCVax-L, CMV-targeted vaccines, and Cancer Transplant Immune Recognition Therapy (CTITR)) provide personalized formulations. CTITR consists of irradiated autologous and allogeneic glioma cells and their lysates, leveraging the inherent immunogenicity of allogeneic material to bypass the need for predefined tumor-specific antigen selection. This strategy promotes broad CD8⁺ T cell expansion, potentially exceeding 10⁹ antigen-specific cytotoxic T lymphocytes, sufficient for substantial tumor clearance. Such a preparation can start with approximately 1 g of surgically resected tumor tissue per patient to generate both autologous and allogeneic vaccine components. Clinical observations indicate that cell-based vaccine preparations can be effective in both newly diagnosed glioblastoma patients treated post-surgery and in patients with recurrent gliomas. Cell-based vaccines, including CTITR, offer novel, antigen-agnostic immunotherapeutic platforms that harness autologous DC and autologous and allogeneic glioma cells, and their lysates bypass the need for predefined tumor-specific antigen selection. Full article

(This article belongs to the Topic Advances in Glioblastoma: From Biology to Therapeutics)

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21 pages, 3884 KB  

Open AccessArticle

CpG ODN Activates TLR9 and Upregulates TLR3 via the p38 MAPK-ATF3 Signaling Axis to Synergistically Enhance Dendritic Cell Vaccine Efficacy

by Lv Zhou, Zhuowei Lei, Qian Jiang, Linpeng Xu, Quanji Wang, Yimin Huang and Ting Lei

Cells 2025, 14(22), 1785; https://doi.org/10.3390/cells14221785 - 13 Nov 2025

Cited by 8 | Viewed by 2324

Abstract

Toll-like receptor 9 (TLR9) and Toll-like receptor 3 (TLR3), which are widely expressed in dendritic cells (DCs), function as key pattern recognition receptors (PRRs) in the immune system. Their primary roles involve specifically detecting pathogen-associated molecular patterns (PAMPs): TLR9 recognizes unmethylated CpG motifs [...] Read more.

Toll-like receptor 9 (TLR9) and Toll-like receptor 3 (TLR3), which are widely expressed in dendritic cells (DCs), function as key pattern recognition receptors (PRRs) in the immune system. Their primary roles involve specifically detecting pathogen-associated molecular patterns (PAMPs): TLR9 recognizes unmethylated CpG motifs predominantly found in bacterial and viral DNA, while TLR3 identifies viral double-stranded RNA (dsRNA), a molecular signature associated with viral replication. Their specific agonists [CpG ODN (a TLR9 agonist) and poly(I:C) (a TLR3 agonist)] can effectively activate DCs and enhance the expression of immune activation-related molecules. In this study, by establishing a mouse primary dendritic cell model and a glioma-bearing mouse model, and employing techniques such as transcriptome sequencing, we found that combined stimulation with CpG ODN and poly(I:C) significantly enhanced the anti-tumor function of DCs: in vitro, DCs subjected to combined stimulation showed upregulation of anti-tumor-related surface markers, enhanced migratory capacity, and a more effective activation of CD8⁺ T cells; in vivo, a DC vaccine loaded with tumor lysate antigen and stimulated with this combined regimen significantly delayed the progression of glioma in tumor-bearing mice. Further investigation revealed that the underlying mechanism for this enhanced effect may involve TLR9 activation promoting TLR3 upregulation through the p38 MAPK-ATF3 signaling axis. Consequently, we designed a sequential stimulation protocol (first CpG ODN then poly(I:C)), which demonstrated a stronger anti-glioma effect compared to simple combined stimulation. This study provides a new strategy for enhancing the immune efficacy of DC vaccines and has potential significance for promoting the clinical translation of DC vaccines. Full article

(This article belongs to the Topic Advances in Glioblastoma: From Biology to Therapeutics)

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22 pages, 322 KB  

Open AccessArticle

New Approach for Enhancing Survival in Glioblastoma Patients: A Longitudinal Pilot Study on Integrative Oncology

by Massimo Bonucci, Maria Pia Fuggetta, Lorenzo Anelli, Diana Giannarelli, Carla Fiorentini and Giampietro Ravagnan

Cancers 2025, 17(14), 2321; https://doi.org/10.3390/cancers17142321 - 12 Jul 2025

Cited by 2 | Viewed by 9182

Abstract

Background: Glioblastoma (GBM IDH-wildtype WHO 2021) is an aggressive central nervous system malignancy with a poor prognosis despite standard therapy. Integrative oncology approaches involving natural compounds have shown potential in preclinical studies to enhance the efficacy of chemoradiotherapy. Methods: This prospective, [...] Read more.

Background: Glioblastoma (GBM IDH-wildtype WHO 2021) is an aggressive central nervous system malignancy with a poor prognosis despite standard therapy. Integrative oncology approaches involving natural compounds have shown potential in preclinical studies to enhance the efficacy of chemoradiotherapy. Methods: This prospective, longitudinal observational pilot study, lacking a randomized control group, followed 72 newly diagnosed glioblastoma patients (diagnosed by histological examination and MGMT promoter molecular study alone, grade 4 glioma patients) treated with the STUPP protocol. This group could voluntarily opt to receive integrative therapy (IT), which included polydatin, curcumin, and Boswellia serrata, in addition to standard care. Survival outcomes were compared between IT-adherent and non-adherent patients. Multivariate Cox regression was employed to adjust for potential confounders, including age, extent of surgical resection, and corticosteroid use. Results: The median overall survival (OS) for the entire cohort was 13.3 months. Patients who adhered to IT (n = 60) had a median OS of 25.4 months, which increased to 34.4 months for those who underwent gross total resection. The non-IT group (n = 12) exhibited a median OS of 10.6 months. Multivariate analysis confirmed that IT adherence and the extent of resection were independent predictors of prolonged survival (p < 0.05). No severe adverse events were reported with IT. Conclusions: Integrative therapy combining polydatin, curcumin, and Boswellia serrata with standard treatment would appear to be associated with prolonged survival in glioblastoma patients, particularly among those who underwent gross total resection. However, the small size of the control group, the absence of randomization, and the inclusion solely of primary glioblastoma limit the generalizability of these findings. These results underscore the need for further investigation through randomized controlled trials. Full article

(This article belongs to the Topic Advances in Glioblastoma: From Biology to Therapeutics)

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