High-grade gliomas (HGGs), particularly glioblastoma (GBM), remain among the most lethal human cancers despite decades of molecular profiling and therapeutic innovation. A primary reason for treatment failure is that HGG biology is spatial: malignant cell states, immune suppression, metabolic stress, and therapeutic resistance are organized into distinct anatomical and functional niches. Spatial omics technologies now enable high-dimensional mapping of gene expression, protein signaling, immune architecture, and metabolic activity within intact tumor tissue. These approaches reveal how proneural and mesenchymal transcriptional states coexist yet localize to distinct regions, alongside hypoxic, invasive, and stem-enriched niches. Spatial analyses show that key clinical determinants, including O6-methylguanine-DNA methyltransferase (MGMT)-associated temozolomide resistance, radiotherapy tolerance in hypoxic regions, and immunotherapy failure driven by myeloid-dominated immune exclusion, are influenced not only by molecular programs but also by cellular location. Beyond biological insight, spatial omics is reshaping clinical paradigms by enabling region-specific patient stratification, early assessment of treatment response, and identification of therapy-resistant reservoirs that seed recurrence. Prior bulk and single-cell studies defined HGG cell states and pathways but often treated resistance as tumor-wide. This review presents a spatially explicit framework that synthesizes spatial transcriptomic and immune-profiling studies to identify tumor-immune niches and spatial bottlenecks that drive therapeutic failure and recurrence.

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults. Although recent World Health Organization classifications integrating molecular features have improved diagnostic precision, therapeutic outcomes for IDH-wild-type glioblastoma remain dismal. Standard treatment with radiotherapy and temozolomide has changed little over the past two decades, and most investigational therapies have failed to produce durable clinical benefit. Tumor heterogeneity, adaptive resistance mechanisms, a profoundly immunosuppressive tumor microenvironment, and limited drug delivery across the blood-brain barrier have collectively contributed to these failures. This review summarizes the evolving molecular landscape of glioblastoma and examines emerging therapeutic approaches designed to overcome these barriers. We discuss advances in molecularly targeted therapies, including strategies directed at BRAF and FGFR alterations, as well as continued efforts to address EGFR-driven disease. We also review immunotherapeutic approaches such as immune checkpoint inhibition, chimeric antigen receptor T-cell therapies, and oncolytic viruses, highlighting key clinical trial results and biological challenges. In parallel, we explore metabolic targeting strategies and novel technologies aimed at improving central nervous system drug delivery, including focused ultrasound and convection-enhanced delivery. Collectively, current evidence indicates that meaningful progress in glioblastoma will require biomarker-driven patient selection, rational combination strategies, and improved methods for intracranial drug delivery. While substantial challenges remain, ongoing translational and clinical efforts provide a framework for the development of more effective and personalized therapeutic strategies.

Glioblastoma (GBM) remains a formidable clinical challenge, characterized by invasive growth, therapeutic resistance, and dismal patient survival. We report the development of HITMAN (highly localized electric field-induced tumor therapy using magnetically actuated nanoantennas), a wireless bioelectric therapy that selectively eradicates GBM cells with cellular precision. Magnetically actuated nanoantennas convert low-frequency (≤200 kHz), deep-brain-penetrant magnetic fields into localized electric fields, thereby triggering protein unfolding, membrane disruption, and ER stress. In vitro, HITMAN demonstrated superior efficacy compared to temozolomide (TMZ), significantly decreasing viability in drug-resistant, patient-derived GBM cells by 52.2%, versus 10% with TMZ while sparing neurons and astrocytes. Mechanistically, HITMAN activated the unfolded protein response and autophagy pathways, suppressed cell cycle and adhesion genes, reduced Ki-67 expression, disrupted cytoskeletal architecture, and elevated p53 levels, underscoring a multifaceted antitumor mechanism. In orthotopic mouse models, HITMAN significantly inhibited tumor growth, extended median survival by more than 50%, and exhibited no systemic toxicity. Thus, HITMAN offers a minimally invasive, spatially precise, and clinically translatable therapy for GBM.

Lactate is increasingly recognized as a central metabolic, epigenetic, and immunoregulatory determinant of glioma biology. In highly glycolytic gliomas, lactate dehydrogenase A (LDHA)-dependent lactate production and monocarboxylate transporter (MCT)-mediated transport support metabolic adaptation and multicellular metabolic crosstalk while contributing to extracellular acidification, immune suppression, and histone and non-histone lactylation. Recent studies have further uncovered subtype- and context-dependent mechanisms linking lactate to immune escape, nucleotide biosynthesis, cGAS-STING suppression, and resistance to temozolomide, radiotherapy, and anti-angiogenic therapy. Importantly, lactate biology differs substantially across molecular subtypes, particularly between isocitrate dehydrogenase (IDH)-wildtype and IDH-mutant gliomas. Despite rapid mechanistic advances, clinical translation remains limited: MCT1 inhibition has reached early-phase clinical evaluation in advanced extracranial malignancies, whereas its relevance to glioma remains unestablished and selective LDHA-directed and lactylation-directed strategies remain predominantly preclinical. This review integrates lactate production and transport, immunometabolic regulation, lactylation, tumor-microenvironment remodeling, and emerging therapeutic strategies within a subtype-aware, mechanism-to-translation framework. We further critically evaluate evidence limitations, therapeutic maturity, metabolic compensation, biomarker requirements, and brain-delivery challenges to define priorities for precision lactate-targeted therapy in glioma.

MALT1 protease is an intracellular signaling molecule that promotes tumor progression via cancer cell-intrinsic and cancer cell-extrinsic mechanisms. MALT1 has been mostly studied in lymphocytes, and little is known about its role in tumor-associated macrophages. We show that MALT1 is expressed in glioblastoma (GBM)-associated macrophages. Mechanistically, GBM tumor cells induce a MALT1-NF-κB signaling axis in macrophages, leading to enhanced macrophage migration and polarization toward an immunosuppressive ('M2-like') phenotype. Inactivation of MALT1 protease promotes transcriptional reprogramming that reduces migration and restores a macrophage anti-tumor 'M1-like' phenotype. Preclinical in vivo analysis shows that MALT1 inhibitor treatment results in immuno-reactivity of GBM-associated macrophages and reduced GBM tumor growth. The addition of MALT1 inhibitor to temozolomide reduces immunosuppression in the tumor microenvironment, indicating that pharmacological inhibition of MALT1 protease may enhance the efficacy of chemotherapeutic. Thus, our findings suggest that MALT1 protease inhibition represents a promising macrophage-targeted immunotherapeutic strategy for the treatment of GBM.

Glioblastoma (GBM) represents the most aggressive primary malignant tumor of the adult central nervous system, with an extremely poor clinical prognosis. As the first-line chemotherapeutic agent for GBM, temozolomide (TMZ) has encountered a critical therapeutic bottleneck due to the development of drug resistance in tumor cells. GBM pathogenesis is jointly driven by multiple factors, including genetics, epigenetics, and the tumor microenvironment. O[6]-methylguanine-DNA methyltransferase (MGMT) -driven repair of DNA alkylation lesions is the central molecular mechanism underlying TMZ resistance in GBM. Beyond this canonical pathway, the maintenance of stemness in glioma stem cells (GSCs), the bidirectional regulation of autophagy, metabolic reprogramming that reshapes redox homeostasis, and multicellular crosstalk in the tumor microenvironment also contribute to the development of drug resistance. Core molecules such as signal transducer and activator of transcription 3 (STAT3), 5'-AMP-activated protein kinase (AMPK), and mammalian target of rapamycin (mTOR) interact to form an intricate signaling network that modulates drug resistance. This review systematically illustrates the regulatory networks governing GBM pathogenesis and TMZ resistance. It dissects signaling cascades of distinct resistance mechanisms and crosstalk between core signaling axes, and identifies key regulatory molecules and druggable targets for each resistance phenotype. It aims to provide a theoretical basis and novel insights for the development of emerging therapeutic strategies, including targeted therapy, immunomodulation, combination therapy, and nanodrug delivery, thereby promoting the establishment of multi-targeted and individualized precision medicine models and laying a foundation for breaking through the bottleneck of GBM chemoresistance and improving the survival prognosis of patients.

Glioblastoma is the most aggressive and common malignant primary brain tumor among adults. Due to its aggressiveness, GBM entails a short median overall survival and fatal outcomes. Incidence notably increases with age, 50% of patients being diagnosed at the age of 65 or older. Given that cognitive loss is commonly confused with age-related cognitive impairment, delays in diagnosis are frequent. Furthermore, the elderly are a vulnerable group, commonly having poorer functional status, more comorbidities, and reduced tolerance to intensive treatments. Therefore, clinical and therapeutic implications should be considered within a multidisciplinary approach. The aim of the present study was to review the current knowledge on the management of glioblastoma in the elderly population (≥ 65 years).

Vimentin intermediate filaments are a hallmark of aggressive tumours and are widely linked to invasion and EMT, yet how vimentin-dependent mechanics shape genome maintenance and therapy response is unclear. Here we show that vimentin, particularly under compressive load, promotes DNA repair competence. In contrast, vimentin-negative cells show impaired DNA damage sensing and downstream signaling, ultimately leading to decreased apoptosis and promoting cell survival under genotoxic stress at the expense of genomic stability. Using controlled cell compression together with genetic and pharmacological perturbations, we find that loss of vimentin in glioblastoma cells limits the expression and activity of core repair pathways because of induced nuclear mechanical compression. Relieving nuclear compression restores DNA damage accumulation and repair kinetics. Functionally, suppression of DNA damage responses enhances survival after clinically relevant DNA-damaging treatments, including temozolomide, X-Ray radiation and cell invasion through tight spaces. These findings invert the prevailing view that vimentin's contribution to tumour progression stems from enhanced migration and identify a mechanochemical vimentin-nucleus axis that tunes DNA damage responses to favor therapy tolerance and genome evolution.

Glioma is a highly aggressive brain tumor with poor prognosis and limited therapeutic options. Although temozolomide (TMZ) remains the standard chemotherapeutic agent for glioma, frequent recurrence and the development of therapeutic resistance continue to limit clinical benefit, highlighting the need for new molecular targets and treatment strategies. Here, we identify neuromedin U receptor 2 (NMUR2) as a driver of glioma progression and a potential therapeutic target. NMUR2 expression was markedly elevated in glioma tissues and positively associated with tumor grade. Functional analyses showed that NMUR2 promoted glioma cell proliferation and migration, whereas NMUR2 silencing attenuated these malignant phenotypes. Mechanistically, NMUR2 activated Gαq-dependent Ca[2+] signaling, leading to STAT5 phosphorylation and subsequent transcriptional upregulation of the cell cycle-associated genes PIM1 and FOXM1. Drug-repurposing screening of 6,331 compounds identified NNC 05-2090 as a candidate NMUR2 antagonist. NNC 05-2090 blocked NMUR2-mediated Gαq/Ca[2+]/STAT5 signaling, which was associated with reduced PIM1 and FOXM1 expression, cell cycle arrest, and suppression of glioma growth in vitro and in vivo. In addition, combination treatment with TMZ produced synergistic anti-tumor effects in glioma models. Collectively, our findings define a previously unrecognized NMUR2/Gαq/STAT5/PIM1-FOXM1 signaling axis in glioma and support pharmacological inhibition of NMUR2 as a potential therapeutic strategy.

Glioblastoma (GBM) is among the most aggressive primary brain tumors, marked by rapid proliferation, therapeutic resistance, and profound intratumoral heterogeneity. Epigenetic regulators such as lysine-specific demethylase 1A (KDM1A) and histone deacetylase 2 (HDAC2) are aberrantly expressed in resistant GBM subpopulations and strongly correlate with poor clinical outcomes. Here, we assessed the therapeutic potential of MPT0G521, a dual KDM1A/class I HDAC inhibitor, in disrupting epigenetic regulation and cell cycle progression. Bioinformatic analyses of resistance-associated gene profiles (temozolomide and 2 Gy radiation) and single-cell transcriptomic datasets from distinct tumor regions revealed enrichment of KDM1A and HDAC2 in high-cycling GBM clusters, particularly at invasive margins prone to recurrence. Functional assays demonstrated that MPT0G521 potently inhibited proliferation of both parental and temozolomide-resistant GBM cells, inducing G2/M arrest and apoptosis. Transcriptomic profiling further identified significant downregulation of centrosome integrity genes (FSD1, KIFC1), spindle regulators (TUBB, STMN1, KIF2C, KIF15), kinetochore components (AURKB, CDCA8, SPAG5), and G2/M checkpoint mediators (CENPF, MYBL2, CCNF, MYT1, CDC25A), resulting in disrupted mitotic progression. Mechanistically, MPT0G521 increased histone H3 methylation and acetylation, validating its dual inhibitory activity against KDM1A and class I HDACs. Collectively, these findings indicate that MPT0G521 disrupts the G2/M activation and mitotic machinery, thereby suppressing proliferative and resistant GBM subpopulations. This dual epigenetic strategy holds strong promise for overcoming GBM heterogeneity and reducing recurrence.