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Updates and Advances in the Field of Glioblastomas: Mechanisms, Microenvironment and Treatments

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 20 April 2026 | Viewed by 3283

Special Issue Editor


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Guest Editor
Institute of Pathology, Ente Ospedaliero Cantonale (EOC), 6900 Locarno, Switzerland
Interests: glioblastoma; immunotherapy; gliomas; miRNA; non-small cell lung cancer; cancer therapy

Special Issue Information

Dear Colleagues,

Despite the many years of effort and research spent searching for new clinical approaches and markers for treating glioblastoma multiforme (GBM), this tumor still remains one of the most common primary malignancies. However, recent years have seen major changes in classification, combined with the increased importance of precise molecular characterization. Significant advances have been reported in the taxonomy, classification, and grading of both adult and pediatric brain gliomas. In addition, the roles of the microenvironment, gene profiling, and molecular research are being further studied to ensure precise diagnoses and identify new treatments. This Special Issue aims to clarify the importance of molecular heterogeneity in GBM, both in adults and children, and to bridge mechanistic discoveries with translational innovation.

We welcome submissions, including original papers and reviews. Since IJMS is a journal of molecular science, pure clinical or model studies are not suitable. However, clinical or pure model submissions with biomolecular experiments are welcome. Our Special Issue will focus on, but is not restricted to, the following:

  • Tumor signatures in primary vs. secondary gliomas;
  • The role of recently identified biomarkers in both the prognosis and treatment of pediatric and adult gliomas;
  • Role of checkpoints inhibitors in low- and high-grade gliomas;
  • Mechanisms of recurrence of high-grade gliomas;
  • Molecular features in low-grade gliomas shifting into high-grade gliomas.

Dr. Samantha Epistolio
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • GBM
  • molecular classification
  • pediatric diffuse gliomas
  • signaling pathways in GBMs
  • recurrent gliomas
  • midbrain gliomas
  • immunotherapy
  • targeted therapies for GBMs

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Published Papers (4 papers)

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Research

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14 pages, 1675 KB  
Article
Necrotic Cells Alter IRE1α-XBP1 Signaling and Induce Transcriptional Changes in Glioblastoma
by Jiwoo Lim, Seulgi Lee, Ye-Seon Hong, Ji Ha Choi, Ala Jo, Jihee Lee Kang, Tae-Jin Song and Youn-Hee Choi
Int. J. Mol. Sci. 2026, 27(1), 474; https://doi.org/10.3390/ijms27010474 - 2 Jan 2026
Viewed by 293
Abstract
Necrosis is a characteristic feature of glioblastoma multiforme (GBM) and is closely associated with tumor-associated inflammation and poor clinical outcomes. However, the molecular consequences of necrotic cell death on endoplasmic reticulum (ER) stress signaling in GBM cells remain unclear. In this study, we [...] Read more.
Necrosis is a characteristic feature of glioblastoma multiforme (GBM) and is closely associated with tumor-associated inflammation and poor clinical outcomes. However, the molecular consequences of necrotic cell death on endoplasmic reticulum (ER) stress signaling in GBM cells remain unclear. In this study, we examined the effects of necrotic cells on the ER stress signaling and unfolded protein response (UPR) in human glioblastoma cell lines. Exposure to necrotic cells reduced IRE1α phosphorylation and increased unspliced XBP1 (XBP1u) accumulation, without affecting PERK or ATF6 pathways. These changes were accompanied by enhanced IκBα phosphorylation and impaired autophagic degradation. Treatment with ER stress inducers failed to reverse XBP1u accumulation, and reduced phosphorylation of PKAc was observed together with decreased IRE1α activation. Transcriptomic analysis and quantitative reverse transcription PCR (qRT-PCR) revealed that necrotic cell-induced XBP1u was associated with altered expression of XBP1-related genes, while XBP1 knockdown produced similar transcriptional changes and enhanced the effects of necrotic cell treatment. These findings suggest that necrotic cells impair canonical IRE1α-XBP1 signaling and induce transcriptional reprogramming in glioblastoma cells, which may contribute to tumor progression. Full article
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31 pages, 11117 KB  
Article
Multiomics Investigation of Exhausted T Cells in Glioblastoma Tumor Microenvironment: CCL5 as a Prognostic and Therapeutic Target
by Ruihao Qin, Menglei Hua, Yaru Wang, Qi Zhang, Yong Cao, Yanyan Dai, Chenjing Ma, Xiaohan Zheng, Kaiyuan Ge, Huimin Zhang, Shi Li, Yan Liu, Lei Cao and Liuying Wang
Int. J. Mol. Sci. 2025, 26(20), 9920; https://doi.org/10.3390/ijms26209920 - 12 Oct 2025
Viewed by 1317
Abstract
Glioblastoma multiforme (GBM) is a common malignancy with poor prognosis, and exhausted T (TEX) cells, a subset of T cells characterized by progressive loss of effector functions, play a critical role in its progression. This study aimed to investigate the impact of TEX-related [...] Read more.
Glioblastoma multiforme (GBM) is a common malignancy with poor prognosis, and exhausted T (TEX) cells, a subset of T cells characterized by progressive loss of effector functions, play a critical role in its progression. This study aimed to investigate the impact of TEX-related genes on immune function, prognosis, and drug sensitivity in GBM through multiomics analysis. Initially, we identified a novel set of TEX-related genes specific to GBM and screened hub genes (CCL5, IL18, CXCR6, FCER1G, TNFSF13B) using conventional statistical methods combined with machine learning. A prognostic risk model was subsequently constructed based on TCGA data and validated in the CGGA cohort. Single-cell and pharmacogenomic analyses revealed significant differences in tumor microenvironment composition and drug sensitivity between risk groups. Notably, Palbociclib emerged as a potential therapeutic agent targeting the novel discovered biomarker CCL5. RT-qPCR results showed that T cells with low CCL5 expression exhibited reduced expression of immune checkpoint-related genes (PD1, TIM3, LAG3) and increased expression of CD28, suggesting enhanced immune function. In conclusion, our findings highlight five hub genes as prognostic markers that could stratify GBM patients with different immune landscapes and levels of drug sensitivity. Furthermore, experimental results suggest that low CCL5 expression could alleviate T cell exhaustion and represent a promising therapeutic target, offering new strategies for improving GBM prognosis. Full article
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21 pages, 5179 KB  
Article
Rat Glioma 101.8 Tissue Strain: Molecular and Morphological Features
by Anna Igorevna Alekseeva, Alexandra Vladislavovna Sentyabreva, Vera Vladimirovna Kudelkina, Ekaterina Alexandrovna Miroshnichenko, Alexandr Vladimirovich Ikonnikov, Elena Evgenievna Kopantseva, Anna Mikhailovna Kosyreva and Timur Khaysamudinovich Fatkhudinov
Int. J. Mol. Sci. 2025, 26(18), 8992; https://doi.org/10.3390/ijms26188992 - 15 Sep 2025
Cited by 2 | Viewed by 1003
Abstract
The search for markers applicable for efficient differential diagnosis and personalized therapy is a priority task of experimental neuro-oncology. Modern molecular methods allow us to analyze human biopsy material; however, further actions with this extracted tumor tissue are limited. Relevant and sophisticated CNS [...] Read more.
The search for markers applicable for efficient differential diagnosis and personalized therapy is a priority task of experimental neuro-oncology. Modern molecular methods allow us to analyze human biopsy material; however, further actions with this extracted tumor tissue are limited. Relevant and sophisticated CNS tumor models are required for precise therapy development. Although it is possible to use human biomaterial to create 2D and 3D cultures and implant them into xenograft animals, the data generated from such models is limited. Due to changes in the classification of the CNS tumors in 2021, a representative model should have not only morphological similarity to human tumors but also key genetic aberrations for studying the mechanisms of carcinogenesis and personalized therapy (such as PDGFRa, Olig1/2, Sox2, and Mki67) for different glioma models such as astrocytoma, oligodendroglioma, and glioblastoma. On the basis of a unique scientific facility “The Collection of experimental tumors of the nervous system and neural tumor cell lines” (Avtsyn Research Institute of Human Morphology of “Petrovsky National Research Center of Surgery”), there is a biobank of chemically induced transplantable tumors of laboratory animals. Their properties, mechanisms, and progression closely correlate with malignant CNS neoplasms in humans. These are potentially useful for identifying novel signaling pathways associated with oncogenesis in the nervous system and personalizing therapeutic approaches. In our work, we characterized a tissue-transplantable brain tumor strain of rat glioma101.8 using MRI, IHC, scRNA-seq, and qPCR-RT methods. According to this study, the cellular composition of the tissue-transplantable rat glioma 101.8 strain was determined, as well as the major genetic signature characteristics of each cell population of this tissue-transplantable strain and its microenvironment. Full article
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Review

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18 pages, 1428 KB  
Review
The Glymphatic–Immune Axis in Glioblastoma: Mechanistic Insights and Translational Opportunities
by Joaquin Fiallo Arroyo and Jose E. Leon-Rojas
Int. J. Mol. Sci. 2026, 27(2), 928; https://doi.org/10.3390/ijms27020928 - 16 Jan 2026
Viewed by 253
Abstract
Glioblastoma (GBM) remains one of the most treatment-resistant human malignancies, largely due to the interplay between disrupted fluid dynamics, immune evasion, and the structural complexity of the tumor microenvironment; in addition to these, treatment resistance is also driven by intratumoral heterogeneity, glioma stem [...] Read more.
Glioblastoma (GBM) remains one of the most treatment-resistant human malignancies, largely due to the interplay between disrupted fluid dynamics, immune evasion, and the structural complexity of the tumor microenvironment; in addition to these, treatment resistance is also driven by intratumoral heterogeneity, glioma stem cell persistence, hypoxia-induced metabolic and epigenetic plasticity, adaptive oncogenic signaling, and profound immunosuppression within the tumor microenvironment. Emerging evidence shows that dysfunction of the glymphatic system, mislocalization of aquaporin-4, and increased intracranial pressure compromise cerebrospinal fluid–interstitial fluid exchange and impair antigen drainage to meningeal lymphatics, thereby weakening immunosurveillance. GBM simultaneously remodels the blood–brain barrier into a heterogeneous and permeable blood–tumor barrier that restricts uniform drug penetration yet enables tumor progression. These alterations intersect with profound immunosuppression mediated by pericytes, tumor-associated macrophages, and hypoxic niches. Advances in imaging, including DCE-MRI, DTI-ALPS, CSF-tracing PET, and elastography, now allow in vivo characterization of glymphatic function and interstitial flow. Therapeutic strategies targeting the fluid-immune interface are rapidly expanding, including convection-enhanced delivery, intrathecal and intranasal approaches, focused ultrasound, nanoparticle systems, and lymphatic-modulating immunotherapies such as VEGF-C and STING agonists. Integrating barrier modulation with immunotherapy and nanomedicine holds promise for overcoming treatment resistance. Our review synthesizes the mechanistic, microenvironmental, and translational advances that position the glymphatic–immune axis as a new frontier in glioblastoma research. Full article
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