Search Results (79)

Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain tumors, largely due to its profound intratumoral heterogeneity and immunosuppressive microenvironment. Various classifications of GBM subtypes were created based on transcriptional and methylation profiles. This effort, followed by the development of new technology such as single-nuclei sequencing (snRNAseq) and spatial transcriptomics, led to a better understanding of the glioma cells’ plasticity and their ability to transition between diverse cellular states. GBM cells can mimic neurodevelopmental programs to resemble oligodendrocyte or neural progenitor behavior and hitchhike the local neuronal network to support their growth. The tumor microenvironment, especially under hypoxic conditions, drives the tumor cell clonal selection, which then reshapes the immune cells’ functions. These adaptations contribute to immune evasion by progressively disabling T cell and myeloid cell functions, ultimately establishing a highly immunosuppressive tumor milieu. This complex and metabolically constrained environment poses a major barrier to effective antitumor immunity and limits the success of conventional therapies. Understanding the dynamic interactions between glioma cells and their microenvironment is essential for the development of more effective immunotherapies and rational combination strategies aimed at overcoming resistance and improving patient outcomes. Full article

Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain tumors, necessitating novel therapeutic approaches. Oncolytic treatments, particularly oncolytic viruses (OVs), have emerged as promising candidates by selectively infecting and lysing tumor cells while stimulating anti-tumor immunity. Various virus-based therapies are under investigation, including genetically engineered herpes simplex virus (HSV), adenovirus, poliovirus, reovirus, vaccinia virus, measles virus, and Newcastle disease virus, each exploiting unique tumor-selective mechanisms. While some, such as HSV-based therapies including G207 and Delytact^TM, have demonstrated clinical progress, significant challenges persist, including immune evasion, heterogeneity in patient response, and delivery barriers due to the blood–brain barrier. Moreover, combination strategies integrating OVs with immune checkpoint inhibitors, chemotherapy, and radiation are promising but require further clinical validation. Non-viral oncolytic approaches, such as tumor-targeting bacteria and synthetic peptides, remain underexplored. This review highlights current advancements while addressing critical gaps in the literature, including the need for optimized delivery methods, better biomarker-based patient stratification, and a deeper understanding of GBM’s immunosuppressive microenvironment. Future research should focus on enhancing OV specificity, engineering viruses to deliver therapeutic genes, and integrating OVs with precision medicine strategies. By identifying these gaps, this review provides a framework for advancing oncolytic therapies in GBM treatment. Full article

The Gliomas account for 81% of all malignant central nervous system tumors and are classified by WHO into four grades of malignancy. Glioblastoma multiforme (GBM), the most common grade IV glioma, exhibits an extremely aggressive phenotype and a dismal five-year survival rate of only 6%, underscoring the urgent need for novel therapeutic approaches. Immunotherapy has emerged as a promising strategy, and photodynamic therapy (PDT) in particular has attracted attention for its dual cytotoxic and immunostimulatory effects. In GBM models, PDT induces immunogenic cell death characterized by the release of damage-associated molecular patterns (DAMPs), which promote antigen presentation and activate T cell responses. Additionally, PDT transiently increases blood–brain barrier permeability, facilitating immune cell infiltration into the tumor microenvironment, and enhances clearance of waste products via stimulation of meningeal lymphatic vessels. Importantly, PDT can reprogram or inactivate immunosuppressive tumor-associated macrophages, thereby counteracting the pro-tumoral microenvironment. Despite these encouraging findings, further preclinical and clinical studies are required to elucidate PDT’s underlying immunological mechanisms fully and to optimize treatment regimens that maximize its efficacy as part of integrated immunotherapeutic strategies against GBM. Full article

IDH-mutant gliomas (IMGs) are a unique subset of diffuse gliomas that follow a relatively indolent course compared to IDH-wildtype glioblastoma (GBM) but inevitably progress, often to a higher histologic grade. Current standard therapies, including surgery, chemoradiation, and the recently approved mutant IDH inhibitor (mIDHi) vorasidenib, provide limited disease control and are not curative. Given the immunosuppressive tumor microenvironment (TME) driven by the mutant IDH enzyme and its associated oncometabolite 2-hydroxyglutarate (2-HG), novel immunotherapies offer a promising avenue for treatment. The goal of this paper is to review the main immunologic characteristics that distinguish IMG from GBM, including reduced T cell infiltration and function, fewer myeloid cells, and increased immune-dampening signaling. We also evaluate the preclinical and clinical evidence for immunotherapeutic approaches with the most potential to induce meaningful clinical activity, such as immune checkpoint inhibitors, CAR T cells, tumor vaccines, myeloid redirection, and oncolytic viruses. Despite significant advances in immunotherapy for IMG, fundamental questions persist, including optimal timing and combination strategies, mechanisms underpinning treatment resistance, and strategies to overcome the suppressive microenvironment. Future exploration of these treatment modalities, with a focus on mitigating soluble immunosuppressive factors in the TME, enhancing in situ T cell persistence, and leveraging novel antigen targets, is critical for advancing the state of therapy for this presently incurable group of tumors. Full article

Glioblastoma (GBM) is a highly aggressive primary brain cancer with dismal prognoses despite current standards of care. Immunotherapy is being explored for GBM, given its promising results in other solid malignancies; however, the results from early clinical studies in GBM are disappointing. It has been discovered that GBM has numerous mechanisms of immune resistance, including the physical blood–brain barrier, high intratumoral and intertumoral heterogeneity, and numerous cellular and molecular components in the tumor microenvironment (TME) that promote immunosuppression. Furthermore, GBM utilizes numerous metabolic pathways to establish a survival advantage in the TME. Recently, it has begun to become evident that these complex metabolic pathways that promote GBM growth and invasion also contribute to tumor immune resistance. Aerobic glycolysis provides tumor cells with ample ATP while depleting key glucose and increasing acidity in the TME. Increased glutamine, tryptophan, and arginine metabolism deprives T cells of these necessary amino acids for proper anti-tumor function. Sphingolipid metabolism promotes an immunosuppressive phenotype in the TME and affects immune cell trafficking. This review will discuss, in detail, the key metabolic pathways relevant to GBM pathophysiology which also modulate host immunosuppression. Full article

GBM is the most common and aggressive primary brain tumor in adults, characterized by low survival rates, high recurrence, and resistance to conventional therapies. Traditional diagnostic and therapeutic methods remain limited due to the difficulty in permeating the blood–brain barrier (BBB), diffuse tumor cell infiltration, and tumor heterogeneity. In recent years, nano-based technologies have emerged as innovative approaches for the detection and treatment of GBM. A wide variety of nanocarriers, including dendrimers, liposomes, metallic nanoparticles, carbon nanotubes, carbon dots, extracellular vesicles, and many more demonstrate the ability to cross the BBB, precisely deliver therapeutic agents, and enhance the effects of radiotherapy and immunotherapy. Surface functionalization, peptide modification, and cell membrane coating improve the targeting capabilities of nanostructures toward GBM cells and enable the exploitation of their photothermal, magnetic, and optical properties. Furthermore, the development of miRNA nanosponge systems offers the simultaneous inhibition of multiple tumor growth mechanisms and the modulation of the immunosuppressive tumor microenvironment. This article presents current advancements in nanotechnology for GBM, with a particular focus on the characteristics and advantages of specific groups of nanoparticles, including their role in radiosensitization. Full article

Background: Glioblastoma (GBM) remains the most aggressive primary brain tumor with limited treatment options. The immunosuppressive tumor microenvironment (TME), largely shaped by tumor-associated macrophages (TAMs), represents a significant barrier to effective immunotherapy. Objective: This review aims to explore the role of TAMs within the TME, highlighting the phenotypic plasticity, interactions with tumor cells, and potential therapeutic targets to enhance anti-tumor immunity. Findings: TAMs constitute a substantial portion of the TME, displaying functional plasticity between immunosuppressive and pro-inflammatory phenotypes. Strategies targeting TAMs include depletion, reprogramming, and inhibition of pro-tumor signaling pathways. Preclinical studies show that modifying TAM behavior can shift the TME towards a pro-inflammatory state, enhancing antitumor immune responses. Clinical trials investigating inhibitors of TAM recruitment, polarization, and downstream signaling pathways reveal promising yet limited results, necessitating further research to optimize approaches. Conclusions: Therapeutic strategics targeting TAM plasticity through selective depletion, phenotypic reprogramming, or modulation of downstream immunosuppressive signals represent promising avenues to overcome GBM-associated immunosuppression. Early clinical trials underscore their safety and feasibility, yet achieving meaningful clinical efficacy requires deeper mechanistic understanding and combinatorial approaches integrating macrophage-direct therapies with existing immunotherapeutic modalities. Full article

Graphene-based materials (GBMs) have shown significant promise in cancer therapy due to their unique physicochemical properties, biocompatibility, and ease of functionalization. Their ability to target solid tumors, penetrate the tumor microenvironment (TME), and act as efficient drug delivery platforms highlights their potential in nanomedicine. However, the complex and dynamic nature of the TME, characterized by metabolic heterogeneity, immune suppression, and drug resistance, poses significant challenges to effective cancer treatment. GBMs offer innovative solutions by enhancing tumor targeting, facilitating deep tissue penetration, and modulating metabolic pathways that contribute to tumor progression and immune evasion. Their functionalization with targeting ligands and biocompatible polymers improves their biosafety and specificity, while their ability to modulate immune cell interactions within the TME presents new opportunities for immunotherapy. Given the role of metabolic reprogramming in tumor survival and resistance, GBMs could be further exploited in metabolism-targeted therapies by disrupting glycolysis, mitochondrial respiration, and lipid metabolism to counteract the immunosuppressive effects of the TME. This review focuses on discussing research studies that design GBM nanocomposites with enhanced biodegradability, minimized toxicity, and improved efficacy in delivering therapeutic agents with the intention to reprogram the TME for effective anticancer therapy. Additionally, exploring the potential of GBM nanocomposites in combination with immunotherapies and metabolism-targeted treatments could lead to more effective and personalized cancer therapies. By addressing these challenges, GBMs could play a pivotal role in overcoming current limitations in cancer treatment and advancing precision oncology. Full article

Attempts to activate an anti-tumor immune response in glioblastoma (GBM) have been met with many challenges due to its inherently immunosuppressive tumor microenvironment. The degree and mechanisms by which molecularly and phenotypically diverse tumor-propagating glioma stem cells (GSCs) contribute to this state are poorly defined. In this study, our multifaceted approach combining bioinformatics analyses of clinical and experimental datasets, single-cell sequencing, and the molecular and pharmacologic manipulation of patient-derived cells identified GSCs expressing immunosuppressive effectors mimicking regulatory T cells (Tregs). We showed that this immunosuppressive Treg-like (ITL) GSC state is specific to the mesenchymal GSC subset and is associated with and driven specifically by TGFβ type II receptor (TGFBR2) in contrast to TGFBR1. Transgenic TGFBR2 expression in patient-derived GBM neurospheres promoted a mesenchymal transition and induced a six-gene ITL signature consisting of CD274 (PD-L1), NT5E (CD73), ENTPD1 (CD39), LGALS1 (galectin-1), PDCD1LG2 (PD-L2), and TGFB1. This TGFBR2-driven ITL signature was identified in clinical GBM specimens, patient-derived GSCs, and systemic mesenchymal malignancies. TGFBR2^high GSCs inhibited CD4+ and CD8+ T cell viability and their capacity to kill GBM cells, effects reversed by pharmacologic and shRNA-based TGFBR2 inhibition. Collectively, our data identify an immunosuppressive GSC state that is TGFBR2-dependent and susceptible to TGFBR2-targeted therapeutics. Full article

Glioblastoma (GBM) is an exceedingly aggressive primary brain tumor defined by rapid growth, extensive infiltration, and resistance to standard therapies. A central factor driving these malignancies is the subpopulation of glioblastoma stem cells (GSCs), which possess self-renewal capacity, multipotency, and the ability to regenerate tumor heterogeneity. GSCs contribute to key hallmarks of GBM pathobiology, including relentless progression, resistance to chemotherapy and radiotherapy, and inevitable recurrence. GSCs exhibit distinct molecular signatures, enhanced DNA repair, and metabolic adaptations that protect them against conventional treatments. Moreover, they reside within specialized niches—such as perivascular or hypoxic microenvironments—that sustain stemness, promote immunosuppression, and facilitate angiogenesis. Recent discoveries highlight signaling pathways like Notch, Wnt/β-catenin, Hedgehog, STAT3-PARN, and factors such as TFPI2 and HML-2 as critical regulators of GSC maintenance, plasticity, and immune evasion. These findings underscore the complexity of GSC biology and their pivotal role in driving GBM heterogeneity and therapeutic failure. Emerging therapeutic strategies aim to target GSCs through multiple avenues, including surface markers, immunotherapeutics (e.g., CAR T cells), metabolic vulnerabilities, and combination regimens. Advances in patient-derived organoids, single-cell omics, and 3D co-culture models enable more accurate representation of the tumor ecosystem and personalized therapeutic approaches. Ultimately, improved understanding of GSC-specific targets and the tumor microenvironment promises more effective interventions, paving the way toward better clinical outcomes for GBM patients. Full article

Gliomas, particularly glioblastoma (GBM), are among the most challenging brain tumors due to their complex and dynamic tumor microenvironment (TME). The TME plays a pivotal role in tumor progression, immune evasion, and resistance to therapy through intricate interactions among glioma cells, immune components, neurons, astrocytes, the extracellular matrix, and the blood-brain barrier. Targeting the TME has demonstrated potential, with immunotherapies such as checkpoint inhibitors and neoadjuvant therapies enhancing immune responses. Nonetheless, overcoming the immunosuppressive landscape and metabolic adaptations continues to pose significant challenges. This review explores the diverse cellular and molecular mechanisms that shape the glioma TME. A deeper understanding of these mechanisms holds promise for providing novel therapeutic opportunities to improve glioma treatment outcomes. Full article

Despite multimodal therapies, the treatment of glioblastoma remains challenging. In addition to the very complex mechanisms of cancer cells, including specialized phenotypes that enable them to proliferate, invade tissues, and evade immunosurveillance, they exhibit a pronounced resistance to chemo- and radiotherapy. More advanced tumors create a hypoxic environment that supports their proliferation and survival, while robust angiogenesis ensures a constant supply of nutrients. In GBM, these structures are very pronounced and contribute to the creation and maintenance of a highly immunosuppressive microenvironment that promotes tumor growth and immune escape. In addition, the high accumulation of immunosuppressive tumor-infiltrating leukocytes and other cells, the pronounced expression of immune checkpoint molecules, and the low mutational burden, i.e., the low number of neoantigens, are hallmarks of GBM and contribute to the challenge of therapeutic approaches. Here, we review a number of mechanisms that GBM exploits to support tumor growth and potential treatments. These include new chemotherapeutics, tumor treating fields, and small molecules, including compounds targeting angiogenesis or blockers of tyrosine kinases that inhibit tumor cell proliferation and survival. In addition, we focus on immunotherapies such as immune checkpoint blockade or cell therapies, in particular vaccination with dendritic cells and CAR-T cells, which can either kill GBM cells directly or bypass immunosuppression by modulating the tumor microenvironment or boosting the patient’s own immune response. Full article

Glioblastoma (GBM) is the most aggressive brain tumor, characterized by high recurrence rates and poor patient outcomes. Treatment failure is driven by multiple factors, including complex tumor heterogeneity, the presence of cancer stem cells, the immunosuppressive tumor microenvironment (TME), and many others. GBM’s heterogeneity underlines its ability to resist therapies and adapt to the TME. The TME, which is highly immunosuppressive and shaped by hypoxia, impairs anti-tumor immunity and limits the efficacy of immunotherapy. The blood–brain barrier (BBB) remains a major obstacle to delivering sufficient drug concentrations to the tumor by restricting the penetration of therapeutic agents. Another problem is the lack of reliable biomarkers to perform better patient stratification or even guide personalized treatments, resulting in generalized therapeutic approaches that do not adequately address GBM complexities. This review highlights the multifactorial nature of GBM treatment failure and highlights the need for a paradigm shift and innovative, personalized strategies. A deeper understanding of tumor biology and advances in translational research will be crucial to developing effective therapies and improving patient outcomes in this devastating disease. Full article

Background: Glioblastoma (GBM) is the most common primary malignant brain tumor, with fewer than 5% of patients surviving five years after diagnosis. The introduction of immune checkpoint inhibitors (ICIs), followed by chimeric antigen receptor (CAR) T-cell therapy, marked major advancements in oncology. Despite demonstrating efficacy in other blood and solid cancers, these therapies have yielded limited success in clinical trials for both newly diagnosed and recurrent GBM. A deeper understanding of GBM’s resistance to immunotherapy is essential for enhancing treatment responses and translating results seen in other cancer models. Objectives: In this review, we examine clinical trial outcomes involving ICIs and CAR-T for GBM patients and explore the evasive mechanisms of GBM and the tumor microenvironment. Findings and Discussion: Multiple clinical trials investigating ICIs in GBM have shown poor outcomes, with no significant improvement in progression-free survival (PFS) or overall survival (OS). Results from smaller case studies with CAR-T therapy have warranted further investigation. However, no large-scale trials or robust studies have yet established these immunotherapeutic approaches as definitive treatment strategies. Future research should shift focus from addressing the scarcity of functional T cells to exploiting the abundant myeloid-derived cells within the tumor microenvironment. Conclusions: Translating these therapies into effective treatments for glioblastoma in humans remains a significant challenge. The highly immunosuppressive nature of GBM and its tumor microenvironment continue to hinder the success of these innovative immunotherapeutic approaches. Targeting the myeloid-derived compartment may lead to more robust and sustained immune responses. Full article

Glioblastoma (GBM) is an aggressive brain tumor characterized by extensive metabolic reprogramming that drives tumor growth and therapeutic resistance. Key metabolic pathways, including glycolysis, lactate production, and lipid metabolism, are upregulated to sustain tumor survival in the hypoxic and nutrient-deprived tumor microenvironment (TME), while glutamine and tryptophan metabolism further contribute to the aggressive phenotype of GBM. These metabolic alterations impair immune cell function, leading to exhaustion and stress in CD8+ and CD4+ T cells while favoring immunosuppressive populations such as regulatory T cells (Tregs) and M2-like macrophages. Recent studies emphasize the role of slow-cycling GBM cells (SCCs), lipid-laden macrophages, and tumor-associated astrocytes (TAAs) in reshaping GBM’s metabolic landscape and reinforcing immune evasion. Genetic mutations, including Isocitrate Dehydrogenase (IDH) mutations, Epidermal Growth Factor Receptor (EGFR) amplification, and Phosphotase and Tensin Homolog (PTEN) loss, further drive metabolic reprogramming and offer potential targets for therapy. Understanding the relationship between GBM metabolism and immune suppression is critical for overcoming therapeutic resistance. This review focuses on the role of metabolic rewiring in GBM, its impact on the immune microenvironment, and the potential of combining metabolic targeting with immunotherapy to improve clinical outcomes for GBM patients. Full article