Glioma-associated macrophages (GAMs) constitute the most abundant subset of immune cells in the glioblastoma (GBM) microenvironment, but the underlying mechanism of intense infiltration needs to be elucidated. In this study, we found that GBM cells secrete ICAM1 via FASN signaling to promote GAM infiltration. FASN expression is correlated with GAM density in GBM patients. In vitro experiments revealed that FASN regulates the type-I interferon pathway, particularly STAT1 expression. Moreover, disrupting FASN-STAT1 signaling through the overexpression or inhibition of FASN or STAT1 in GBM cells strongly influences microglial recruitment. Additionally, ICAM1 acts as a direct transcriptional candidate of FASN-STAT1 and a paracrine soluble factor, recruiting microglia to GBM tumors. This study revealed crosstalk between GBM cells and GAMs through FASN-STAT1-ICAM1 signaling to promote microglial infiltration, suggesting potential strategies for treating GBM patients.

Cancer stem cells (CSCs) represent a distinct subpopulation of cancer cells that orchestrate cancer initiation, progression, metastasis, and therapeutic resistance. Despite advances in conventional therapies, the persistence of CSCs remains a major obstacle to achieving cancer eradication. Nanomedicine-based approaches have emerged for precise CSC targeting and elimination, offering unique advantages in overcoming the limitations of traditional treatments. This review systematically analyzes recent developments in nanomedicine for CSC-targeted therapy, emphasizing innovative nanomaterial designs addressing CSC-specific challenges. We first provide a detailed examination of CSC biology, focusing on their surface markers, signaling networks, microenvironmental interactions, and metabolic signatures. On this basis, we critically evaluate cutting-edge nanomaterial engineering designed to exploit these CSC traits, including stimuli-responsive nanodrugs, nanocarriers for drug delivery, and multifunctional nanoplatforms capable of generating localized hyperthermia or reactive oxygen species. These sophisticated nanotherapeutic approaches enhance selectivity and efficacy in CSC elimination, potentially circumventing drug resistance and cancer recurrence. Finally, we present an in-depth analysis of current challenges in translating nanomedicine-based CSC-targeted therapies from bench to bedside, offering critical insights into future research directions and clinical implementation. This review aims to provide a comprehensive framework for understanding the intersection of nanomedicine and CSC biology, contributing to more effective cancer treatment modalities.

Central nervous system (CNS) cancers, particularly glioblastoma (GBM), are associated with high mortality and disability rates. Despite aggressive surgical resection, radiotherapy, and chemotherapy, patient survival remains poor. The blood-brain barrier (BBB) significantly impedes therapeutic efficacy, making BBB penetration a critical focus of research. Focused ultrasound (FUS) combined with microbubbles (MBs) can transiently open the BBB through mechanisms such as cavitation, modulation of tight junction protein expression, and enhanced vesicular transport in endothelial cells. This review highlights precision delivery and personalized treatment strategies under ultrasound visualization, including precise control of ultrasound parameters and modulation of the immune microenvironment. We discuss the applications of ultrasound-responsive nanoparticles in brain tumor therapy, including enhanced radiotherapy, gene delivery, immunotherapy, and sonodynamic therapy (SDT), with a particular emphasis on piezoelectric catalytic immunotherapy. Finally, we provide insights into the clinical translation potential of ultrasound-responsive nanoparticles for personalized and precision treatment of brain tumors.

Near-infrared photoimmunotherapy (NIR-PIT) is a promising cancer treatment that uses near-infrared light to activate a conjugate of a monoclonal antibody (mAb) and a photoactivatable silica phthalocyanine dye (IRDye700DX: IR700). Unlike conventional photodynamic therapy (PDT), NIR-PIT selectively destroys targeted tumor cells while preserving the surrounding normal tissue and providing superior tissue penetration. Recently, NIR-PIT has been approved for the treatment of unresectable recurrent head and neck cancers in Japan. It induces highly selective cancer cell death; therefore, it is expected to be a new curative treatment option for various cancers, including brain tumors. In this review, we compare the principles of NIR-PIT and PDT and discuss the potential applications of NIR-PIT for brain tumors. We selected targetable proteins across various types of brain tumors and devised a strategy to effectively pass the mAb-IR700 conjugate through the blood-brain barrier (BBB), which is a significant challenge for NIR-PIT in treating brain tumors. Innovative approaches for delivering the mAb-IR700 conjugate across the BBB include exosomes, nanoparticle-based systems, and cell-penetrating peptides. Small-molecule compounds, such as affibodies, are anticipated to rapidly accumulate in tumors within intracranial models, and our preliminary experiments demonstrated rapid uptake. NIR-PIT also induces immunogenic cell death and activates the anti-tumor immune response. Overall, NIR-PIT is a promising approach for treating brain tumors. It has the potential to overcome the limitations of conventional therapies and offers new hope to patients with brain tumors.

Interactions between tumors and adjacent blood vessels are critical in the tumor microenvironment (TME) for influencing angiogenesis and hematogenous metastasis. Understanding these interactions within the native TME is vital for targeting various tumors, including brain tumors, due to the complexities of the blood-brain barrier. Developing an accurate tumor model that includes cell-cell and cell-matrix interactions, as well as blood flow-induced shear stress, is essential for high-throughput screening (HTS) of anti-cancer drugs. Here, we developed a glioblastoma (GBM) model surrounded by vascular cells. The arterial model was constructed by encapsulating GBM spheroids with layers of human smooth muscle cells (SMCs) and human umbilical vein endothelial cells (HUVECs), while the capillary cell layered model used only HUVECs. Comparative analysis with tumors from different organs revealed the significant role for platelet endothelial cell adhesion molecule (PECAM) in GBM-blood vascular cell interactions. Cytokine secretion analysis demonstrated PECAM's impact on tumor-specific angiogenic potential. Testing with anti-cancer drugs revealed increased expression of PECAM-associated proteins, drug resistance cytokines, and genes associated with tumor progression and metastasis. Additionally, we developed a HTS platform by encapsulating these tumor models in hydrogels and subjecting them to media circulation, effectively mimicking the dynamic TME, suitable for cancer treatment research and drug development.

Glioma is a highly lethal tumor with a poor prognosis, in which the presence of the blood-brain barrier (BBB) and skull significantly limits treatment options. To address this, a tumor-implantable optofluidic system (LED-SC), consisting of a microsized LED (microLED) and a microsyringe chip (SC), is proposed to deliver both light and prodrug nanoparticles (PNPs) directly to brain glioma. The LED-SC combines microLED and SC to enable intratumoral administration of light and PNPs for chemophotodynamic therapy. PNPs, self-assembled nanoparticles of verteporfin (VPF)-doxorubicin (DOX) prodrug, are cleaved by the enzyme cathepsin B, releasing active drugs specifically within tumor cells. In vitro studies show that PNPs are taken up by glioma cells and exhibit enhanced cytotoxicity under light irradiation. The PNPs-loaded LED-SC can be implanted into glioma, wherein PNPs are slowly diffused through the tumor, bypassing the BBB, and it also ensures effective light delivery in glioma beneath the skull, boosting chemo-photodynamic therapy. In glioma mouse models, PNP-loaded LED-SC implantation showed a 3.9-fold improvement in PNP delivery efficiency over intravenous administration, leading to better drug distribution and therapeutic results. The PNPs-loaded LED-SC offers a promising and minimally invasive solution for glioma treatment, overcoming the barriers of the BBB and skull while reducing systemic toxicity.

Exosomes (Exos), nanosized membranous vesicles (30-160 nm), have been validated as an effective drug delivery system capable of traversing biological barriers. Mesenchymal stem cells (MSCs), due to their near-limitless self-renewal capabilities, provide a plentiful source of exosomes for clinical applications. In this study, we utilized an exosome-encapsulated rapamycin (Exo-Rapa) delivery strategy, which permits the use of smaller drug dosages to achieve effects typically seen with higher dosages, thus enhancing drug efficacy. Moreover, Exos can transport pharmaceuticals across the blood-brain barrier (BBB) to the brain, and further penetrate GL261 cells to exert their effects. Within the tumor microenvironment, Exo-Rapa is released more rapidly and efficiently at the tumor site. The acidic conditions in tumors accelerate the release of Exo-Rapa, a characteristic that may make it a promising targeted therapeutic in future cancer research. Additionally, a series of in vivo experiments have further demonstrated the permeability of Exo-Rapa across the BBB, enabling it to accumulate at tumor sites; it also ameliorates inflammatory responses in Glioblastoma multiforme (GBM) mouse models and enhances anti-tumor activity through the regulation of angiogenesis via the VEGF/VEGFRs axis. Our results indicate that MSC-derived exosomes are a potent therapeutic carrier for GBM, offering an effective strategy for enhancing drug delivery across the BBB and providing a scientific foundation for the use of exosomes in the treatment of GBM and other diseases.

The blood-brain barrier (BBB) is crucial for brain homeostasis but is a major obstacle in delivering anticancer drugs to brain tumors. However, this perspective requires re-evaluation, particularly for malignant brain tumors, such as gliomas and brain metastases. In these aggressive tumors, the BBB undergoes significant alterations, leading to the formation of a more permeable blood-tumor barrier. While this increased permeability allows better drug penetration, heterogeneity in blood-tumor barrier (BTB) integrity across different tumor regions remains a challenge. Additionally, the main challenge in treating brain tumors lies not in BBB penetration but in the lack of effective drugs. Conventional chemotherapies, including temozolomide and nitrosourea agents, have shown limited efficacy, and resistance mechanisms often reduce their long-term benefits. The "BBB curse" has often been blamed for the slow progress in drug development. However, emerging evidence suggests that even larger-molecule therapies, such as antibody-drug conjugates, can successfully target brain tumors. This review aims to critically reassess the roles of the BBB and BTB in brain tumor therapy, highlighting their impact on drug delivery and evaluating the current landscape of chemotherapeutic strategies. Furthermore, it explores new approaches to overcome treatment limitations, emphasizing the need for personalized and targeted therapeutic strategies.

Glioma, a highly malignant central nervous system tumor, exhibits aggressive invasiveness, extensive infiltration, and poor prognosis. Conventional treatments such as surgery, radiotherapy, and chemotherapy are hindered by limitations including the inability to overcome the blood-brain barrier (BBB), drug resistance, and high recurrence rates. Ferroptosis induced by nanoparticle-based systems offers an innovative strategy for glioma therapy by efficiently traversing the BBB, precisely delivering ferroptosis inducers, enhancing tumor accumulation, and enabling stimuli-responsive drug release. These features collectively improve the induction efficiency of ferroptosis in glioma cells. Various nanoplatforms, including inorganic nanoparticles, biomimetic carriers, and polymer-based systems, have demonstrated potential in crossing the BBB, inducing ferroptosis, and suppressing glioma progression. These systems enhance reactive oxygen species generation, deplete glutathione, and disrupt tumor microenvironment defense mechanisms, achieving synergistic therapeutic effects. The integration of ferroptosis with nanotechnology is emerging as a promising, non-invasive strategy for the treatment of gliomas, offering substantial therapeutic potential.

Lactate, the end product of glycolysis, plays a crucial role in cellular signaling and metabolism. The discovery of lactylation, a novel post-translational modification, has uncovered the role of lactate in regulating diseases, especially in the brain. Lactylation connects genetic encoding with protein function, thereby influencing key biological processes. Increasing evidence supports lactate-mediated lactylation as a critical modulator in neurological disorders. This review offers an overview of lactate metabolism and lactylation, highlighting recent advances in understanding the regulatory enzymes of lactylation and their role in the central nervous system. We investigate the impact of lactylation on brain dysfunctions, including neurodegenerative diseases, cerebrovascular disorders, neuroinflammation, brain tumors, and psychiatric conditions. Moreover, we highlight the therapeutic potential of targeting lactylation in treating brain disorders and outline key research gaps and future directions needed to advance this promising field.

High-Mobility Group A1 (HMGA1) is a chromatin-associated protein involved in regulating key cellular processes, including DNA transcription, replication, recombination, and repair. It is highly expressed during embryogenesis and reactivated in various cancers, where it contributes to tumor progression and metastasis. We investigated the prognostic significance of HMGA1 gene expression in gliomas by comparing its expression in normal brain tissue and different glioma grades.

Real-time quantitative PCR (qPCR) was performed on 75 glioma samples obtained from Aga Khan University Hospital (Pakistan), along with 10 Normal Adjacent Tissue (NAT) samples. The correlation between HMGA1 expression and prognosis was evaluated using Kaplan-Meier (KM) plotter in glioma patients. Statistical analyses were conducted using the R platform and further validated through the online database Chinese Glioma Genome Atlas (CGGA) using online tools.

HMGA1 expression was significantly upregulated in gliomas compared to NAT (p < 0.001) and increased with tumor grade (p = 0.015). High HMGA1 expression correlated with Ki-67 levels and was associated with worse survival (p = 0.0014). Patients with elevated HMGA1 had a 3.5-fold higher mortality risk (95% CI: 1.5-7.9, p = 0.003). ROC analysis yielded an AUC of 0.752, indicating its potential prognostic value.

HMGA1 overexpression is associated with poor prognosis in gliomas, suggesting its potential as a prognostic marker. However, further validation is needed to confirm its clinical utility.

Glioblastoma is a fatal primary malignant brain tumor. Despite therapies involving surgical resection, chemotherapy, and radiation therapy, the average survival for glioblastoma patients remains at approximately 15 months. MicroRNAs (miRNAs) are short noncoding RNA molecules that regulate the expression of the majority of human genes. Numerous genes are concurrently deregulated in glioblastoma. Consequently, molecular monotherapies have failed to achieve improvements in clinical outcomes. Several lines of evidence suggest that simultaneous targeting of several deregulated molecules is required to achieve better therapies. However, the simultaneous targeting of several deregulated oncogenic drivers is severely limited by the fact that the drugs needed to target many deregulated molecules do not currently exist, and because combining several drugs in a clinical setting leads to an exponential increase in toxicity. We hypothesized that we can develop and use miRNA to simultaneously inhibit multiple deregulated genes for more efficacious glioblastoma therapies. The goal of this study was therefore to identify master regulatory microRNAs (miRNAs) and use them to simultaneously target multiple deregulated molecules for GBM therapy. We defined master regulatory miRNAs as those that target several deregulated genes in glioblastoma. To find master regulatory miRNAs, we first used PAR-CLIP screenings to identify all targets of all miRNAs in glioblastoma cells. We then analyzed TCGA tumor data to determine which of these targets are deregulated in human tumors. We developed and used an algorithm to rank these targets for significance in glioblastoma malignancy based on their magnitude of deregulation, frequency of deregulation, and correlation with patient survival. We then ranked the miRNAs for their capacity of targeting multiple glioblastoma-deregulated genes and therefore the potential to exhibit strong anti-tumor effects when delivered as therapy. Using this strategy, we selected two tumor suppressor master regulatory miRNAs, miR-340, miR-382 and an oncogenic master regulatory miRNA, miR-17. We validated the target genes of the miRNAs and showed that they form part of important glioblastoma regulatory pathways. We then showed that the miRNAs (miR-340 and miR-582) or the miR-17 inhibitor have strong inhibitory effects on glioblastoma cell growth, survival, invasion, stemness and in vivo tumor growth. Ultimately, we developed and successfully tested a new therapeutic approach to delivery miR-340 using MRI guided focused ultrasound and microbubbles (FUS-MB) and special brain penetrating nanoparticles (BPN). This approach resulted in a substantial reduction in tumor volume and prolongation of the survival of glioblastoma-bearing mice and can be translated into clinical trials. We therefore developed and successfully tested a novel strategy to discover and deliver miRNAs for glioblastoma and cancer therapy.

Heat-shock protein 70 (HSP70) and nanotechnology have emerged as promising avenues in glioblastoma multiforme (GBM) therapy, addressing the critical challenges posed by its aggressive nature and therapeutic resistance. HSP70's dual role in cellular stress response and tumour survival emphasises its potential as both a biomarker and therapeutic target. This review explores the innovative integration of HSP70 with nanotechnology, emphasising advancements in imaging, drug delivery and combination therapies. Nanoparticles, including SPIONs, liposomes, gold nanoparticles and metal-organic frameworks, demonstrate enhanced targeting and therapeutic efficacy through HSP70 modulation. Functionalized nanocarriers exploit HSP70's tumour-specific overexpression to improve drug delivery, minimise off-target effects and overcome the blood-brain barrier. Emerging strategies such as chemophototherapy, immunotherapy and photothermal therapy leverage HSP70's interactions within the tumour microenvironment, enabling synergistic treatment modalities. The review also highlights translational challenges, including heterogeneity of GBM, regulatory hurdles and variability in the enhanced permeability and retention (EPR) effect. Integrating computational modelling, personalised approaches and adaptive trial designs is crucial for clinical translation. By bridging nanotechnology and molecular biology, HSP70-targeted strategies hold transformative potential to redefine GBM diagnosis and treatment, offering hope for improved survival and quality of life. Trial Registration: ClinicalTrials.gov identifier: NCT00054041 and NCT04628806.

Glioblastoma Multiforme is an aggressive and complex cancer affecting mostly elderly patients above the age of 60 years. Originally classified as the fourth stage of glioma, it has an abysmal prognosis along with limited therapeutic options. Surgical removal of tumors, radiotherapy, and chemotherapy are prevalent treatment strategies with numerous therapeutic obstacles, including undefined boundary of tumor mass leaving traces even after excision, chances of secondary cancer formation, and presence of blood-brain barrier. These blood-brain and blood-brain tumor barriers actively restrict the permeability of many molecules from blood circulation to enter the central nervous system. Therefore, many conventional antineoplastic drugs fail to reach the tumor periphery except temozolomide. Meanwhile, active stem cells in the tumor microenvironment, genetic mutation inducing tumor growth, and epigenetic pattern alteration make this cancer chemoresistant. Our review delineates the recent approaches to resensitize the existing clinical drugs through specifically designed nanoformulations. Nanoparticles with modified physiological characteristics and modified through technological parameters can reduce the tumor's stemness, which increases tumor cells' apoptosis rate. Moreover, these nanoparticles can efficiently traverse the blood-brain barrier and escape from endosomal degradation with minimum toxicological impact. Overall, this review discusses the cancer chemoresistance phenomena and related pathways and highlights the potential of nanoformulation in reversing chemoresistance. Also, the existing limitations of this unique approach and suggestions are discussed at the end of the article, which may facilitate the identification of new directions for advancement of the nanoparticle-mediated reversal of chemoresistance.

Background/Objectives: The low permeability of the blood-brain barrier (BBB) represents a significant challenge to effective systemic chemotherapy for primary and metastatic brain cancers. Kinin receptors play a crucial role in modulating BBB permeability, and their agonist analogs have been explored in preclinical animal models to enhance drug delivery to the brain. In this study, we investigated whether des-Arg9-bradykinin (DBK), a physiological agonist of kinin B1 receptor (B1R), acts as a brain drug delivery adjuvant by promoting the transient opening of the BBB. Methods: Human brain microvascular endothelial cells (HBMECs) were treated with DBK in the culture medium and in conditioned media from glioblastoma cell lines, namely T98G (CMT98G) and U87MG (CMU87). Immunofluorescence, RT-qPCR, in-cell Western assay, and proximity ligation assay (PLA) were performed to analyze BBB components, kinin receptors and TLR4, a receptor associated with the kinin pathway and inflammation. The effect of DBK on enhancing paracellular molecule transport was evaluated using Evans blue dye (EB) quantification in a cell culture insert assay and in an in vivo model, where mice with and without brain tumors were treated with DBK. To assess the functional impact of the transient BBB opening induced by DBK, the chemotherapeutic drug doxorubicin (DOX) was administered. Results: Treatment with DBK facilitates the presence of EB in the brain parenchyma by transiently disrupting the BBB, as further evidenced by the increased paracellular passage of the dye in an in vitro assay. B1R activation by DBK induces transient BBB opening lasting less than 48 h, enhancing the bioavailability of the DOX within the brain parenchyma and glioma tumor mass. The interaction between B1R and TLR4 is disrupted by the secreted factors released by glioblastoma cells, as conditioned media from T98G and U87 reduce TLR4 staining in endothelial cells without affecting B1R expression. Conclusions: These results further support the potential of B1R activation as a strategy to enhance targeted drug delivery to the brain.

Glioblastoma (GBM) is a lethal central nervous system tumor, characterized by extensive genomic alterations and high intra-tumoral heterogeneity. Gene fusions, derived from chromosomal translocations, deletions, and inversions, were increasingly recognized as key carcinogenic events, with the highest frequency of FGFR-TACC fusion in glioblastoma. As reported, FGFR3-TACC3 fusion mostly coexists with wild-type IDH status, and associates with better prognosis. Mechanistically, FGFR3-TACC3 fusions can constitutively activate non-canonical FGFR downstream pathways, induce aneuploidy, and participate in mitochondrial metabolism, thereby promoting cell proliferation and tumorigenesis. These functions, whether based on FGFR3 phosphorylation or not, are predominantly attributed to the specific domain of TACC3 that involved in regulating the localization and activation of fusion products. Several preclinical studies and clinical trials are being performed to evaluate the efficacy and safety of the FGFR-TACC fusion as a personalised therapeutic target, including the treatments with tyrosine kinase inhibitors, metabolic inhibitors, HSP90 inhibitors, coiled-coil peptide-mimetics, and targeted protein degraders. A subset of populations with FGFR-TACC-positive glioblastoma, after refined molecular screening strategies, may benefit from targeted therapies. Despite major progress in biotechnology, our understanding on the role of fusion events in glioblastoma represented by the FGFR-TACC is still in its infancy. Here, we highlight recent progress on FGFR-TACC fusion in human glioblastoma, emphasizing their molecular mechanisms and potential clinical value.

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.

The presence of hypoxic regions in tumors is associated with malignancy and is an important target for the high-precision diagnosis and treatment of tumors. Radioresistant hypoxic regions can be precisely identified and treated without the use of high doses of radiation if hypoxic region-specific contrast agents have a therapeutic effect. In this study, we synthesized a therapeutic-diagnostic complex agent (SPION-PG-NI) by combining polyglycerol-functionalized superparamagnetic iron oxide nanoparticles (SPION-PG, core diameter of 8.8 ± 1.9 nm) as an MRI contrast agent and 2-nitroimidazole (NI, a pimonidazole derivative) as a hypoxia-targeted ligand to visually evaluate hypoxic regions using MRI and improve radiotherapy efficacy at those sites. SPION-PG-NI showed a concentration-dependent contrast effect and had significantly higher accumulation in subcutaneous glioblastomas than the control agent, SPION-PG, 24 h after administration. Immunohistological evaluations showed that the SPION-PG-NI-accumulated regions corresponded well to hypoxic regions. SPION-PG-NI showed neither migration into the brain parenchyma nor neurotoxicity. Both SPION-PG and SPION-PG-NI decrease reactive oxygen species (ROS); however, they improve radiotherapy efficacy in hypoxic glioblastoma cells due to cytotoxicity. This effect of SPION-PG-NI was significantly higher than that of SPION-PG (p < 0.01). After 12 Gy irradiation, the mean normalized glioblastoma tumor volume on day 38 in the SPION-PG-NI group (288%) was significantly lower than that in the control group (882%) (p < 0.05). Collectively, these findings suggest the potential of SPION-PG-NI as a useful and safe tumor theranostic nanodevice for hypoxic imaging and improving radiotherapy efficacy.

Despite recent advancements in neuro-oncology, glioblastoma remains one of the cancers with the poorest prognosis. Tumor recurrence and progression are driven by tumor stem cells and a high mutational burden. New potential treatment modalities are actively being explored. One promising approach is focused ultrasound (FUS), which involves converging ultrasound waves on a specific region of interest while avoiding damage to surrounding tissue. This mini-review highlights the current understanding of glioblastoma treatment resistance and positions FUS as a promising therapeutic option. We discuss existing clinical research utilizing FUS in four key treatment applications: (1) blood-brain barrier disruption, (2) histotripsy, (3) thermal ablation, and (4) sonodynamic therapy.

There remain several intractable challenges for chemotherapy in glioma treatment, including the blood-brain barrier (BBB), blood-brain tumor barrier (BBTB), and tumor heterogeneity caused by cancer stem cells (CSCs), which are resistant to conventional chemotherapy. Here, we established a nano strategy to kill glioma cells and CSCs, combining carfilzomib and bis(diethyldithiocarbamate)copper. The synergistic drug combination disturbed cell protein metabolism at different stages and induced apoptosis and cuproptosis. The Y-shaped targeting ligand pHA-VAP-modified nanodiscs were designed to help the chemotherapeutic agents cross the BBB/BBTB and finally accumulate in tumor site. This all-stage targeting and all-stage treatment nanomedicine significantly prolonged the survival in glioma-bearing mice and might inspire the rational design of advanced drug delivery platforms.

Central nervous system (CNS) diseases are a major cause of disability and death worldwide. Due to the blood-brain barrier (BBB), drug delivery for CNS diseases is extremely challenging. Nano-delivery systems can overcome the limitations of BBB to deliver drugs to the CNS, improve the ability of drugs to target the brain and provide potential therapeutic methods for CNS diseases. At the same time, the choice of different drug delivery methods (bypassing BBB or crossing BBB) can further optimize the therapeutic effect of the nano-drug delivery system. This article reviews the different methods of nano-delivery systems to overcome the way BBB enters the brain. Different kinds of nanoparticles to overcome BBB were discussed in depth.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, characterized by rapid proliferation, extensive infiltration, and significant intratumoral heterogeneity. Despite advancements in conventional treatments, including surgery, radiotherapy, and chemotherapy, the prognosis for GBM patients remains poor, with a median survival of approximately 15 months. Immunotherapy has emerged as a promising alternative; however, the unique biological and immunological features, including its immunosuppressive tumor microenvironment (TME) and low mutational burden, render it resistant to many immunotherapeutic strategies. This review explores the key challenges in GBM immunotherapy, focusing on immune evasion mechanisms, the blood-brain barrier (BBB), and the TME. Immune checkpoint inhibitors and CAR-T cells have shown promise in preclinical models but have limited clinical success due to antigen heterogeneity, immune cell exhaustion, and impaired trafficking across the BBB. Emerging strategies, including dual-targeting CAR-T cells, engineered immune cells secreting therapeutic molecules, and advanced delivery systems to overcome the BBB, show potential for enhancing treatment efficacy. Addressing these challenges is crucial for improving GBM immunotherapy outcomes.

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor associated with poor survival outcomes and is driven by a complex tumor microenvironment (TME) that promotes tumor progression and treatment resistance. To explore the role of the TME in GBM, we analyzed glioma-related microarray and single-cell RNA sequencing (scRNA-seq) datasets from the Gene Expression Omnibus (GEO). Functional enrichment and weighted gene coexpression network analyses revealed distinct immune profiles, metabolic alterations, and differences in chemotherapeutic drug sensitivity between the high-risk and low-risk patient groups. scRNA-seq data processed with the 'Seurat' package were used to identify differentially expressed genes in pericytes, endothelial cells, and glioma cells, particularly those involved in extracellular matrix (ECM) remodeling. A 17-gene prognostic signature developed through Cox regression and LASSO analyses revealed that key genes (COL1A1, COL4A1, and VIM) were significantly associated with survival outcomes in GBM patients. Drug sensitivity analyses using data from the Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Therapeutics Response Portal (CTRP) identified potential targeted therapies for GBM, including SB-505,124, staurosporine, and AZD8186. This integrative study underscores the critical roles of the ECM and synaptic remodeling in GBM and suggests novel therapeutic targets to improve personalized treatment strategies for GBM patients.

Intracranial tumors encompass a heterogeneous group of neoplasms, including gliomas, meningiomas, pituitary adenomas, schwannomas, craniopharyngiomas, ependymomas, medulloblastomas, and primary central nervous system lymphomas. These tumors present significant challenges due to their diverse molecular characteristics, critical locations, and the unique obstacles posed by the blood-brain barrier (BBB) and blood-tumor barrier (BTB), which limit the efficacy of systemic therapies. Recent advances in molecular biology and genomics have enabled the identification of specific molecular pathways and targets, paving the way for innovative precision therapies. This review examines the current state of targeted therapies for intracranial tumors, including receptor tyrosine kinase (RTK) inhibitors, PI3K/AKT/mTOR inhibitors, RAF/MEK/ERK pathway inhibitors, IDH mutation inhibitors, immune checkpoint inhibitors, and CAR-T cell therapies. Emphasis is placed on the role of the BBB and BTB in modulating drug delivery and therapeutic outcomes. Strategies to overcome these barriers, such as focused ultrasound, nanoparticle-based delivery systems, and convection-enhanced delivery, are also explored. Furthermore, the manuscript reviews clinical trial data, highlighting successes and limitations across different tumor types. It delves into emerging therapeutic approaches, including combination of regimens and personalized treatments based on molecular profiling. By synthesizing the latest research, this article aims to provide a comprehensive understanding of the advancements and ongoing challenges in the targeted treatment of intracranial tumors. The findings underscore the necessity for innovative delivery systems and more extensive clinical trials to optimize therapeutic strategies. This review aspires to inform future research and clinical practices, aiming to improve patient outcomes and quality of life in the management of these complex and life-threatening conditions.

Background: Intra-arterial cerebral infusion (IACI) of radiotherapeutics is a promising treatment for glioblastoma (GBM) recurrence. We investigated the in silico feasibility and safety of Yttrium-90-Poly(vinyl alcohol)-Microbubble (90Y-PVA-MB) IACI in patients with recurrent GBM and compared the results with those of external beam radiation therapy (EBRT). Methods: Contrast-enhanced T1-weighted magnetic resonance imaging (T1W-MRI) was used to delineate the tumor volumes and CT scans were used to automatically segment the organs at risk in nine patients with recurrent GBM. Volumetric Modulated Arc Therapy (VMAT) treatment plans were generated using a clinical treatment planning system. Assuming the relative intensity of each voxel from the MR-T1W as a valid surrogate for the post-IACI 90Y-PVA-MB distribution, a specific 90Y dose voxel kernel was obtained through Monte Carlo (MC) simulations and convolved with the MRI, resulting in a 90Y-PVA-MB-based dose distribution that was then compared with the VMAT plans. Results: The physical dose distribution obtained from the simulation of 1GBq of 90Y-PVA-MBs was rescaled to ensure that 95% of the prescribed dose was delivered to 95% or 99% of the target (i.e., A95% and A99%, respectively). The calculated activities were A95% = 269.2 [63.6-2334.1] MBq and A99% = 370.6 [93.8-3315.2] MBq, while the mean doses to the target were 58.2 [58.0-60.0] Gy for VMAT, and 123.1 [106.9-153.9] Gy and 170.1 [145.9-223.8] Gy for A95% and A99%, respectively. Additionally, non-target brain tissue was spared in the 90Y-PVA-MB treatment compared to the VMAT approach, with a median [range] of mean doses of 12.5 [12.0-23.0] Gy for VMAT, and 0.6 [0.2-1.0] Gy and 0.9 [0.3-1.5] Gy for the 90Y treatments assuming A95% and A99%, respectively. Conclusions: 90Y-PVA-MB IACI using MR-T1W appears to be feasible and safe, as it enables the delivery of higher doses to tumors and lower doses to non-target volumes compared to the VMAT approach.

Photodynamic therapy (PDT) has emerged as a promising adjunctive treatment for glioblastoma (GBM), yet a comprehensive bibliometric analysis of this field is lacking. This study explores research trends, major contributors, and hotspots in PDT for GBM to provide an integrated overview of its development.

Literature from 1993 to 2024 was retrieved from the Web of Science Core Collection. Bibliometric tools, including CiteSpace, analyzed publication trends, collaborations, and keyword co-occurrence to identify influential authors, institutions, and journals.

A total of 799 publications showed a growing research interest, peaking in 2022. The United States and China were leading contributors, with prominent institutions like the University of California System and Centre National de la Recherche Scientifique. Influential figures, such as Jiro Akimoto and Walter Stummer, advanced clinical applications and fluorescence-guided techniques. Early studies of PDT for GBM have focused on evaluating its efficacy and potential side effects, while recent research has transitioned toward innovative strategies like targeted drug delivery, nanotechnology, and combination therapies. However, the similarities between early and recent studies are in the search for safe and reliable photosensitizers. Keyword analysis highlighted "5-aminolevulinic acid", "in vitro", and "polyethylene glycol compounds" as key areas, while timeline analysis revealed shifts from foundational photosensitizer research to approaches addressing tumor heterogeneity and resistance.

This study provides a systematic overview of PDT research for GBM, spotlighting breakthroughs and collaborative networks. The findings emphasize the importance of innovation and clinical translation to fully realize PDT's potential in GBM therapy.

Glioma is a prevalent form of primary malignant central nervous system tumor, characterized by its cellular invasiveness, rapid growth, and the presence of the blood-brain barrier (BBB)/blood-brain tumor barrier (BBTB). Current therapeutic approaches, such as chemotherapy and radiotherapy, have shown limited efficacy in achieving significant antitumor effects. Therefore, there is an urgent demand for new treatments. Therapeutic peptides represent an innovative class of pharmaceutical agents with lower immunogenicity and toxicity. They are easily modifiable via chemical means and possess deep tissue penetration capabilities which reduce side effects and drug resistance. These unique pharmacokinetic characteristics make peptides a rapidly growing class of new therapeutics that have demonstrated significant progress in glioma treatment. This review outlines the efforts and accomplishments in peptide-based therapeutic strategies for glioma. These therapeutic peptides can be classified into four types based on their anti-tumor function: tumor-homing peptides, inhibitor/antagonist peptides targeting cell surface receptors, interference peptides, and peptide vaccines. Furthermore, we briefly summarize the results from clinical trials of therapeutic peptides in glioma, which shows that peptide-based therapeutic strategies exhibit great potential as multifunctional players in glioma therapy.

Brain metastasis (BM) from colon cancer is associated with a poor prognosis and restricted treatment alternatives, largely due to issues related to blood-brain barrier (BBB) permeability and the negative effects of standard chemotherapy. Nanotechnology improves treatment efficacy by enabling targeted and controlled drug delivery. This review article evaluates the potential of nanotechnology-based therapies for treating colon cancer BM, emphasizing their capacity to cross the BBB, diminish metastatic growth, and enhance overall survival rates. A review of multiple studies evaluated nanoparticles (NPs) as carriers for chemotherapy, focusing on parameters including particle size, surface charge, and drug-loading capacity. The study also reviewed studies that examined BBB penetration, in vitro tumor accumulation, and in vivo tumor growth inhibition. In vitro findings indicated that NPs accumulate more efficiently in BM tissue than in healthy brain tissue and show significant BBB penetration. In vivo, nanotherapy markedly inhibited tumor growth and prolonged survival relative to conventional chemotherapy or control treatments while also exhibiting reduced side effects. Recent studies demonstrated that plant extracts can effectively and safely synthesize nanomaterials, positioning them as a viable and environmentally friendly precursor for nanomaterial production. Nanotechnology-based therapies demonstrate significant potential in the treatment of colon cancer BM by minimizing systemic toxicity, enhancing therapeutic efficacy, and facilitating more targeted drug delivery. Further research is required to confirm these findings and implement them in clinical practice.

Glioblastoma multiforme (GBM) is a highly aggressive and malignant brain tumor originating from glial cells, characterized by high recurrence rates and poor patient prognosis. The heterogeneity and complex biology of GBM, coupled with the protective nature of the blood-brain barrier (BBB), significantly limit the efficacy of traditional therapies. The rapid development of nanoenzyme technology presents a promising therapeutic paradigm for the rational and targeted treatment of GBM. In this review, the underlying mechanisms of GBM pathogenesis are comprehensively discussed, emphasizing the impact of the BBB on treatment strategies. Recent advances in nanoenzyme-based approaches for GBM therapy are explored, highlighting how these nanoenzymes enhance various treatment modalities through their multifunctional capabilities and potential for precise drug delivery. Finally, the challenges and therapeutic prospects of translating nanoenzymes from laboratory research to clinical application, including issues of stability, targeting efficiency, safety, and regulatory hurdles are critically analyzed. By providing a thorough understanding of both the opportunities and obstacles associated with nanoenzyme-based therapies, future research directions are aimed to be informed and contribute to the development of more effective treatments for GBM.

Glioblastoma represents the most aggressive type of brain cancer with minimal clinical advancements in recent decades attributed to the absence of efficient drug delivery strategies. In this study, we synthesized a series of vanadium complexes (V1-V4) and then constructed a lactoferrin (LF)-V4 nanoparticle (NP) delivery system. The nanoplatform crossed the blood-brain barrier by binding to low-density lipoprotein receptor-associated protein-1 and selectively targeted glioblastoma, ultimately inhibiting the growth of in situ glioblastoma tumors. LF-V4 NPs induced autophagic cell death in U87-MG cells by generating reactive oxygen species (ROS) that damaged the mitochondria. Further studies revealed that LF-V4 NPs triggered lipid peroxidation through the accumulation of ROS, the depletion of GSH, and the downregulation of GPX4 and SLC7A11, ultimately leading to ferroptosis in glioblastoma cells.

The central nervous system (CNS) diseases are major contributors to death and disability worldwide. However, the blood-brain barrier (BBB) often prevents drugs intended for CNS diseases from effectively crossing into the brain parenchyma to deliver their therapeutic effects. The blood-brain barrier is a semi-permeable barrier with high selectivity. The BBB primarily manages the transport of substances between the blood and the CNS. To enhance drug delivery for CNS disease treatment, various brain-based drug delivery strategies overcoming the BBB have been developed. Among them, nanoparticles (NPs) have been emphasized due to their multiple excellent properties. This review starts with an overview of the BBB's anatomical structure and physiological roles, and then explores the mechanisms, both endogenous and exogenous, that facilitate the NP passage across the BBB. The text also delves into how nanoparticles' shape, charge, size, and surface ligands affect their ability to cross the BBB and offers an overview of different nanoparticle classifications. This review concludes with an examination of the current challenges in utilizing nanomaterials for brain drug delivery and discusses corresponding directions for solutions. This review aims to propose innovative diagnostic and therapeutic approaches for CNS diseases and enhance drug design for more effective delivery across the BBB.

The prognosis for patients with glioblastoma multiforme (GBM), an aggressive and deadly brain tumor, is poor due to the limited therapeutic options available. Biomimetic nanoparticles have emerged as a promising vehicle for targeted mRNA vaccine delivery, thanks to recent advances in nanotechnology. This presents a novel treatment method for GBM. This review explores the potential of using biomimetic nanoparticles to improve the specificity and effectiveness of mRNA vaccine against GBM. These nanoparticles can evade immune detection, cross the blood-brain barrier, & deliver mRNA directly to glioma cells by mimicking natural biological structures. This allows glioma cells to produce tumor-specific antigens that trigger strong immune responses against the tumor. This review discusses biomimetic nanoparticle design strategies, which are critical for optimizing transport and ensuring targeted action. These tactics include surface functionalization and encapsulation techniques. It also highlights the ongoing preclinical research and clinical trials that demonstrate the therapeutic advantages and challenges of this strategy. Biomimetic nanoparticles for mRNA vaccine delivery represent a new frontier in GBM treatment, which could impact the management of this deadly disease and improve patient outcomes by integrating cutting-edge nanotechnology with immunotherapy.

Localization in the central nervous system, diffuse growth, the presence of stem cells, and numerous resistance mechanisms, all make glioblastoma (GBM) an incurable tumor. The standard treatment of GBM consisting of surgery; radio- and chemotherapy with temozolomide provides insufficient therapeutic benefit and needs to be updated with effective modern solutions. One of the most promising and intensively explored therapeutic approaches against GBM is the use of nanotherapy. The first, and so far only, nanoparticle-based therapy approved for GBM treatment is NanoThermTM. It is based on iron oxide nanoparticles and the thermal ablation of the tumor with a magnetic field. Numerous other types of nanotherapies are being evaluated, including polymer and lipid-based nanoformulations, nanodiscs, dendrimers, and metallic, silica, or bioderived nanoparticles, among others. The advantages of these nanoscale drug carriers include improved penetration across the blood-brain barrier, targeted drug delivery, biocompatibility, and lower systemic toxicity, while major problems with their implementation involve scaling up their production and high costs. Nevertheless, taking all the impressive benefits of nanotherapies into consideration, it seems obvious that the combined effort of the scientific world will need to be taken to tackle these challenges and implement these novel therapies into clinics, giving hope that the battle against GBM can finally be won.

Glioblastoma multiforme (GBM) is considered to be one of the most devastating brain tumors with a shorter life expectancy. Several factors contribute to the dismal prognosis of GBM patients including the complicated nature of GBM, the ability of tumor cells to resist treatment, and the difficulty of delivering drugs to the brain because of barriers like the blood-brain barrier (BBB) and blood-tumor barrier (BTB). The unique challenges posed by the BBB in delivering therapeutic agents to the brain have led to the development of innovative nanotechnology-based approaches. By exploiting the olfactory/trigeminal pathway, nanosystems offer a promising strategy for targeted drug delivery to the brain, glioblastoma tumors in particular. This review contemplates varied nanocarriers, including polymeric nanoparticles, lipid-based nanosystems, in situ gel formulations, peptide, and stem cell-based nanoformulations, signifying their utility in brain targeting with minimal systemic side effects. Emerging trends in gene therapy and immunotherapy in the context of GBM treatment have also been discussed. Since safety is a paramount aspect for any drug product to get approved, this review also delves into toxicological considerations associated with intranasal delivery of nanosystems. Regulatory aspects and critical factors for the successful development of intranasal products are also explored in this review. Overall, this review underscores the significant advancements in nanotechnology for nose-to-brain delivery and its potential impact on GBM management.

The authors present a comprehensive review on the history and development of oncolytic herpes simplex viral therapies for malignant glioma with a focus on mechanisms of delivery in prior and ongoing clinical trials. This review highlights the advancements made with regard to delivering these therapies to a highly complex immunologic environment in the setting of the blood-brain and blood-tumor barrier in a safe and effective manner.

Through transcriptomic analysis of patient-derived glioblastoma tissues, we identify an overactivation of inflammatory pathways that contribute to the development of a tumor-promoting microenvironment and therapeutic resistance. To address this critical mechanism, we present NanoAid, a biomimetic nanoplatform designed to target inflammatory pro-tumor processes to advance glioblastoma chemotherapy. NanoAid employs macrophage-membrane-liposome hybrids to optimize the delivery of COX-2 inhibitor parecoxib and paclitaxel. By inheriting macrophage characteristics, NanoAid not only efficiently traverses the blood-brain barrier and precisely accumulates within tumors but also enhances cancer cell uptake, thereby improving overall anticancer efficacy. Notably, the combination of parecoxib and paclitaxel effectively disrupts inflammatory pro-tumor processes while inducing a synergistic effect that inhibits tumor growth, overcomes therapeutic resistance, and minimizes adverse effects. This results in substantial tumor growth inhibition and extends the median survival of tumor-bearing mice. Thus, our study bridges clinical insights with fundamental research, potentially revolutionizing tumor therapy paradigms.

Background: The multiple drug-resistant phenomenon has long since plagued the effectiveness of various chemotherapies used in the treatment of patients with glioblastoma (GBM), which is still incurable to this day. ATP-binding cassette (ABC) transporters function as drug transporters and have been touted to be the main culprits in developing resistance to xenobiotic drugs in GBM. Methods: This review systematically analyzed the efficacy of ABC transporters against various anticancer drugs from 16 studies identified from five databases (PubMed, Medline, Embase, Scopus, and ScienceDirect). Results: Inhibition of ABC transporters, especially ABCB1, improved drug efficacies. Staple GBM phenotypes, such as GBM stem cells and increased activation of the PI3K/Akt/NF-κB pathway, have been implicated in the expression of several ABC transporters. Using the datasets in The Cancer Genome Atlas and Gene Expression Omnibus, we found upregulated ABC transporters that either negatively impacted survival in univariate analyses (ABCA1, ABCA13, ABCB9, ABCD4) or were independent negative prognosis factors for patients with GBM (ABCA13, ABCB9). Our multivariate analysis further demonstrated three ABC transporters, ABCA13 (Hazard Ratio (HR) = 1.31, p = 0.017), ABCB9 (HR = 1.26, p = 0.03), and ABCB5 (HR = 0.77, p = 0.016), with the administration of alkylating agents (HR = 0.41, p < 0.001), were independent negative prognosis factors for patients with GBM. Conclusions: These findings reinforce the important role played by ABC transporters, particularly by ABCA13, ABCB9, and ABCB1, which could be potential targets that warrant further evaluations for alternate strategies to augment the effects of existing alkylating agents and xenobiotic drugs.

Background: Cerebral intra-arterial chemotherapy (CIAC) has been demonstrated to achieve tumoricidal concentrations in cerebral tumour cells that are otherwise unachievable due to the presence of the blood-brain barrier. In this study, we sought to analyze the safety of CIAC in a cohort of patients treated at the Centre intégré universitaire de santé et de services sociaux de l'Estrie-Centre hospitalier universitaire de Sherbrooke (CIUSSS-CHUS). Methods: Treatments consisted of monthly CIAC. A neurological examination and neuroimaging study (MRI) were performed before every treatment. The files of patients enrolled in our CIAC programme were reviewed. Adverse events were analyzed and categorized. Results: Overall, 2991 CIAC procedures were performed in 642 patients. Pathologies were as follows: malignant gliomas (68.7%), cerebral metastasis (17.6%), and cerebral lymphomas (13.7%). Perfusion vessels were as follows: 80% internal carotid artery and 20% vertebral artery. The chemotherapeutic agents used were carboplatin (86.4%), methotrexate (28.5%), melphalan (28.6%), and liposomal doxorubicin (2.8%). Osmotic blood-brain barrier disruption (BBBD) was induced in 30.5% of treatments. Symptomatic vascular adverse events occurred during 27 procedures (0.9%) in 26 patients (4%). Namely, 23 strokes, one carotid artery occlusion (responsible for one of the strokes), and two intratumoral and one subdural hemorrhage. The absolute risk of stroke was 1.3% and 0.5% for CIAC with or without BBBD, respectively. The use of the vertebral artery significantly increased the risk of stroke. Drug infusion-related seizures occurred in 2.5% of patients; 83.8% were associated with methotrexate and 16.2% with carboplatin. Conclusions: CIAC is a safe procedure with a 0.9% overall rate of symptomatic complications (stroke, carotid occlusion, subdural hemorrhage or intratumoral bleeding-n = 27/2991) on a treatment basis, mainly consisting of strokes (85%, n = 23), with a modified NIH Stroke Scale score of 4.1 ± 3.3.

Porous silicon is one of the most explored nanostructured materials in various biomedical applications owing to its remarkable properties. However, its inherent chemical instability mandates a robust surface modification procedure, and proper surface bioengineering is essential to ensure its effectiveness in the biomedical field. In this study, we introduce a one-pot functionalization strategy that simultaneously stabilizes porous silicon nanoparticles and decorates their surface with carbohydrates through hydrosilylation chemistry, combining mild temperatures and a Lewis acid catalyst. This approach yielded a surface functionalization degree of 300 μmol g-1 in just 4 hours at 60 °C, significantly reducing both the prolonged reaction times and high temperatures typically associated with conventional hydrosilylation. Furthermore, this advancement opens the way for utilizing thermolabile molecules useful for surface bioengineering.

Glioblastoma (GBM), the most prevalent primary malignant brain tumor, remains challenging to treat due to extensive inter- and intra-tumor heterogeneity. This variability demands combination treatments to improve therapeutic outcomes. A significant obstacle in treating GBM is the expression of O6-methylguanine-DNA methyltransferase, a DNA repair enzyme that reduces the efficacy of the standard alkylating agent, temozolomide, in about 50% of patients. This underscores the need for novel, more targeted therapies. Our study investigates the metabolic-epigenetic impact of combining SN-38, a novel topoisomerase inhibitor inducing DNA double-strand breaks, with rabusertib, a checkpoint kinase 1 inhibitor. We identified this synergistic combination through high-throughput drug screening across a panel of GBM cell lines using a cancer drug library combined with SN-38. A secondary metabolic screening with the PEDS algorithm demonstrated a synergistic modulation of purine, one-carbon, and redox metabolism. Furthermore, the combined treatment led to the significant depletion of epigenetically relevant metabolites such as 5-methyl-cytosine, acetyl-lysine, and trimethyl-lysine. Reduced intermediates of the glutathione cycle indicated increased cellular stress following combinatorial treatment. Overall, the combination of SN-38 and rabusertib synergistically disrupts metabolites associated with epigenetic adaptations, leading to cytotoxicity independent of O6-methylguanine-DNA methyltransferase status, thereby underpinning this combination as a promising candidate for combinatorial therapy in GBM.