The present review explores the complex epigenetic mechanisms such as DNA methylation, histone modification and RNA editing that drive GBM progression, shape the tumor microenvironment and facilitate immune evasion and highlights the therapeutic potential of targeting these epigenetic vulnerabilities through inhibitors of histone deacetylase and DNA methyltransferase.
Abstract
Glioblastoma (GBM) is an intricate intracranial tumor that has cataclysmic outlook. It originates from glial cells having an average life expectancy of one and a half years. Despite intensive multimodal therapy, the tumor's innate invasiveness and cellular heterogeneity lead to nearly inevitable recurrence. Recent advancements have shifted the focus toward the interplay between genetic drivers and the dynamic epigenetic landscape. WHO classification defined GBM as an IDH-wildtype tumor, distinguishing it from IDH-mutant. Present review explores the complex epigenetic mechanisms such as DNA methylation, histone modification and RNA editing that drive GBM progression, shape the tumor microenvironment and facilitate immune evasion. The review further discusses severe translational barriers, including blood brain barrier penetrance, tumor heterogeneity, and the immunosuppressive effects of steroids. Finally, we highlight the therapeutic potential of targeting these epigenetic vulnerabilities through inhibitors of histone deacetylase and DNA methyltransferase, either alone or combined with modern immunotherapies to overcome treatment resistance and improve patient outcomes.
Despite advancements in the field of cancer treatment, its efficacy in tackling central nervous system (CNS) tumors – glioblastomas – remains blunted. This review explores the multifactorial reasons behind these tumors’ resistance to immunotherapeutic strategies, with emphasis on the role of the tumor microenvironment, low mutational burden, and immune exclusion. Emerging immune phenotypes – such as inflamed, excluded, and desert types – have varying contributions to the degree of response. Recent advances in immune profiling, including single-cell RNA sequencing and spatial transcriptomics, have begun to pave the way for a deeper understanding of the immunosuppressive architecture of these tumors, revealing the involvement of tumor-associated macrophages, myeloid-derived suppressor cells, and T-regulatory populations. Additionally, we examine the impact of tumor-nerve crosstalk, T-cell exhaustion, and the limited ability of PD-L1 and tumor-mutation burden as predictive markers. The review also highlights the newfound therapeutic strategies – including CAR-T cell therapy and bispecific antibodies – that aim to overcome immune resistance. By integrating insights from immunogenomics, epigenetics, and radiogenomics, we propose a framework for understanding and potentially reversing immune resistance in CNS tumors. This review highlights the urgent need to develop specific, biomarker-informed approaches that would aim to improve outcomes in this domain of neuro-oncology.
S. Beniwal, Rafael Everton Assunção Ribeiro da Costa, A. A. Hanchate et al.· Annals of Medicine and Surge...· 0 citations
A narrative review summarizes the major signaling pathways implicated in GBM pathogenesis, including EGFR, PI3K/AKT/mTOR, Wnt, and TGF-β signaling, while also discussing emerging therapeutic targets such as FGFR3–TACC3 fusions, regorafenib, and natural killer cell-based immunotherapy.
William W Li, J. Chen, Yiying Ma· Future Science OA· 0 citations
The therapeutic landscape of targeted therapies in glioblastomas is summarized, spanning major target classes including receptor tyrosine kinases, intracellular signalling proteins, cell-cycle dysregulation and synthetic-lethal vulnerabilities and emerging strategies targeting genome integrity and telomeres, epigenetic modulators, and tumour-neural circuitry are examined.
E. Aquilanti, M. Touat, P. French et al.· Nature Reviews Clinical Onco...· 0 citations
A narrative review comprehensively summarizes the advances achieved between 2016 and 2026 in GBM-directed gene therapy, focusing on the engineering principles, biological characteristics, and translational applications of viral vectors including retroviral, adenoviral, and adeno-associated viral systems.
Alper Demirezen, Sumeyye Seher Karaman· International Journal of Med...· 0 citations
Since the introduction of the hallmarks of cancer framework over 25 years ago, treatment approaches have evolved into personalized medicine, offering benefits to select patient populations. However, three major components of heterotypic interactions in cancer—mutational evolution of cancer stem cells, epithelial-mesenchymal plasticity (EMP), and cancer-remodeled extracellular matrix (ECM)—remain critical barriers to therapy, particularly in patients who have failed treatment. EMP encompasses a spectrum of to-and-fro transitions between mesenchymal and epithelial states, yielding hybrid phenotypes of evolutionary heterogeneity. These are embedded in the vascular, metabolic, mutational, and immune-suppressive reprogramming of the tumor microenvironment (TME), induced and advanced by the hypoxia–reactive oxygen species (ROS)–hypoxia-inducible factor-1α (HIF-1α)–transforming growth factor-β (TGF-β) signaling axis. This review systematically examines the molecular mechanisms underlying EMP, tumor heterogeneity, and the hallmarks of cancer. It explores pharmacological strategies to target tumor burden, epigenetically revert transitional states, and restore immune-editing functions. Based on this analysis, we propose a phased anti-hallmark Combinations, Timing, and Sequencing (CTS) protocol. The methodology integrates vascular normalization, epigenetic modifiers, trimodal radiotherapy or stereotactic body radiotherapy (SBRT), chemotherapy (CT), and immunotherapy optimization, aiming to improve outcomes while minimizing toxicities. Also, mechanistically, by reverting mesenchymal phenotypes and normalizing the vasculature, the CTS protocol is designed to rescue the immune-suppressive tumor microenvironment—curtailing the recruitment of myeloid-derived suppressor cells (MDSCs) and regulatory T (Treg) cells. This restores cytotoxic T-cell homing, thereby converting immunologically “cold” tumors into “hot,” immunotherapy-responsive lesions.
Kumara Swamy, Guruaj Arakeri, Ramaswamy Veena et al.· Frontiers in Immunology· 0 citations
This review synthesizes key advances in understanding tumor heterogeneity: from its cellular origins and molecular mechanisms to its multidimensional manifestation in the tumor microenvironment and from metastatic heterogeneity to the fundamental causes of treatment resistance.
Jianhong Zhang, Heng Li, S. Ru et al.· Signal Transduction and Targ...· 1 citation
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