Immunotherapy has emerged as a promising approach in the treatment of glioblastoma (GBM), particularly through the use of chimeric antigen receptor (CAR) T cells and immune checkpoint inhibitors. A notable study demonstrated the locoregional infusion of HER2-specific CAR T cells in pediatric patients with recurrent or refractory CNS tumors, showing enhanced therapeutic efficacy due to the engineering of a medium-length CAR spacer (ref: Vitanza doi.org/10.1038/s41591-021-01404-8/). This approach is currently being evaluated in the ongoing BrainChild-01 clinical trial, which aims to assess the safety and efficacy of repetitive locoregional dosing. Additionally, the role of immune checkpoint blockade was explored in recurrent GBM, revealing significant inter-patient and intra-tumor heterogeneity in treatment responses, which was analyzed using advanced multiplex spatial protein profiling and machine learning techniques (ref: Lu doi.org/10.1038/s41467-021-24293-4/). These findings highlight the complexity of the tumor microenvironment and the need for personalized treatment strategies. Moreover, the combination of immunovirotherapy targeting CD137 and PD-L1 has shown promise in inducing a potent and durable antitumor immune response in GBM models (ref: Puigdelloses doi.org/10.1136/jitc-2021-002644/). This study emphasizes the potential of oncolytic viruses in overcoming the immunosuppressive nature of GBM. Contradictory findings regarding the role of DNA-PK in glioma stem cell differentiation and radiation sensitization were also reported, indicating that inhibiting DNA-PK can lead to GSC differentiation and increased sensitivity to radiation (ref: Fang doi.org/10.1126/scitranslmed.abc7275/). Collectively, these studies underscore the evolving landscape of immunotherapy in GBM and the necessity for further research to optimize treatment regimens.

The molecular mechanisms underlying glioblastoma (GBM) progression and therapeutic resistance are complex and multifaceted. Recent studies have focused on the role of glioblastoma stem-like cells (GSCs) and their interactions with the tumor microenvironment. For instance, pericytes have been shown to enhance GBM cell resistance to temozolomide through CCL5-CCR5 paracrine signaling, indicating a critical role of the perivascular niche in mediating chemoresistance (ref: Zhang doi.org/10.1038/s41422-021-00528-3/). Furthermore, the identification of YTHDF2 as a regulator of mRNA decay in GSCs highlights the importance of post-transcriptional modifications in maintaining GSC properties (ref: Chai doi.org/10.1186/s13045-021-01124-z/). Additionally, the exploration of metabolic pathways has revealed that lipolysis of lipid droplets, regulated by CHK1, is essential for the survival of GBM cells under glucose deprivation (ref: Yang doi.org/10.1016/j.molcel.2021.06.013/). This metabolic adaptation may inform therapeutic strategies targeting energy metabolism in GBM. The study of genetic alterations, such as homozygous MTAP deletion, has also been pivotal in identifying potential vulnerabilities in GBM, although recent findings suggest that this deletion does not correlate with elevated levels of methylthioadenosine as previously thought (ref: Barekatain doi.org/10.1038/s41467-021-24240-3/). Overall, these insights into the molecular mechanisms and biomarkers of GBM provide a foundation for developing targeted therapies and improving patient outcomes.

Therapeutic resistance in glioblastoma (GBM) is a significant challenge, often attributed to the tumor microenvironment and the presence of cancer stem cells (CSCs). Recent studies have elucidated the role of pericytes in augmenting GBM cell resistance to temozolomide through CCL5-CCR5 signaling, which enhances DNA damage repair mechanisms in tumor cells (ref: Zhang doi.org/10.1038/s41422-021-00528-3/). This finding underscores the importance of the perivascular niche in mediating chemoresistance and suggests that targeting this interaction may improve treatment efficacy. Moreover, the impact of dietary factors on CSC populations has been investigated, revealing that a high-fat diet can promote aggressive tumor behavior and CSC enrichment in GBM models (ref: Silver doi.org/10.1172/JCI138276/). This highlights the potential for lifestyle interventions to influence tumor biology and treatment outcomes. Additionally, the exploration of metabolic pathways, such as the role of lipid droplet lipolysis in tumor cell survival, further emphasizes the intricate relationship between the tumor microenvironment and therapeutic resistance (ref: Yang doi.org/10.1016/j.molcel.2021.06.013/). Collectively, these studies illustrate the multifactorial nature of therapeutic resistance in GBM and the need for innovative strategies to overcome these challenges.

Advancements in drug delivery systems are crucial for improving therapeutic outcomes in glioblastoma (GBM), a highly aggressive brain tumor. Recent studies have focused on the development of targeted delivery systems, such as glycosylated PAMAM dendrimers, which enhance tumor macrophage targeting and specificity (ref: Sharma doi.org/10.1016/j.jconrel.2021.07.018/). This approach aims to minimize off-site toxicities commonly associated with conventional therapies, thereby improving patient safety and treatment efficacy. Exosomes and biomimetic nanovesicles have also emerged as promising vehicles for brain drug delivery due to their ability to cross the blood-brain barrier (BBB). A head-to-head comparison study demonstrated that autologous biomimetic nanovesicles could serve as effective alternatives to exosomes for delivering therapeutic agents to brain tumors (ref: Wu doi.org/10.1016/j.jconrel.2021.07.004/). Furthermore, the systematic review of local drug delivery systems highlights the ongoing efforts to optimize therapeutic strategies for GBM, emphasizing the need for innovative approaches to enhance drug efficacy and patient outcomes (ref: Bastiancich doi.org/10.1016/j.jconrel.2021.07.031/). These developments in drug delivery systems represent a significant step forward in the quest to improve treatment for GBM patients.

Genetic and epigenetic alterations play a pivotal role in the pathogenesis of glioblastoma (GBM), influencing tumor behavior and treatment responses. Recent studies have identified various molecular targets and pathways that contribute to GBM progression. For instance, the delivery of an oncolytic adenovirus via neural stem cells has shown promise in a phase 1 clinical trial, highlighting the potential of gene therapy approaches in treating high-grade gliomas (ref: Fares doi.org/10.1016/S1470-2045(21)00245-X/). Additionally, the investigation of mitochondrial reactive oxygen species has revealed their role in impairing GSC survival and tumor growth, suggesting that targeting oxidative stress may offer therapeutic benefits (ref: Buccarelli doi.org/10.1186/s13046-021-02031-4/). Moreover, the exploration of co-deregulated microRNA signatures across different CNS tumors has provided insights into common oncogenic mechanisms, which may aid in the identification of novel biomarkers for diagnosis and prognosis (ref: Lambrou doi.org/10.3390/cancers13123028/). The interaction of curaxin CBL0137 with G-quadruplex DNA oligomers further emphasizes the complexity of genetic regulation in GBM, suggesting that targeting DNA structures may represent a novel therapeutic strategy (ref: Dallavalle doi.org/10.3390/ijms22126476/). Collectively, these findings underscore the importance of understanding genetic and epigenetic alterations in GBM to develop targeted therapies and improve patient outcomes.

Clinical trials and real-world evidence are essential for evaluating the efficacy and safety of novel therapies in glioblastoma (GBM). A recent multicenter study reported on the real-world experience of using Depatuxizumab Mafodotin in combination with temozolomide for recurrent GBM patients, providing valuable insights into treatment outcomes outside of controlled clinical trial settings (ref: Padovan doi.org/10.3390/cancers13112773/). This study highlights the importance of integrating real-world data to inform clinical practice and guide treatment decisions. Additionally, the evaluation of AGuIX nanoparticles in a multimodal imaging study has demonstrated their potential as radiosensitizing agents in GBM treatment (ref: Tran doi.org/10.1002/adhm.202100656/). The findings from this study underscore the need for innovative imaging techniques to assess drug delivery and therapeutic efficacy in real-time. Furthermore, the exploration of curaxin CBL0137's interaction with G-quadruplex DNA oligomers adds to the understanding of its antitumor activity, suggesting potential applications in clinical settings (ref: Dallavalle doi.org/10.3390/ijms22126476/). Overall, these studies emphasize the critical role of clinical trials and real-world evidence in advancing GBM treatment and improving patient outcomes.

The biology of glioblastoma (GBM) is intricately linked to the presence of cancer stem cells (CSCs), which contribute to tumor maintenance, progression, and therapeutic resistance. Recent research has focused on the role of neural stem cells in delivering oncolytic adenoviruses, demonstrating promising results in a phase 1 clinical trial for newly diagnosed high-grade gliomas (ref: Fares doi.org/10.1016/S1470-2045(21)00245-X/). This approach highlights the potential of utilizing CSCs for targeted therapies that can effectively combat GBM. Moreover, the investigation of mitochondrial reactive oxygen species has revealed their detrimental effects on GSC survival and tumor growth, suggesting that oxidative stress may be a viable therapeutic target (ref: Buccarelli doi.org/10.1186/s13046-021-02031-4/). The establishment of a syngeneic glioblastoma mouse model for CyberKnife irradiation has also provided insights into the radiobiological effects of high-dose radiation, furthering our understanding of treatment responses in GBM (ref: Jelgersma doi.org/10.3390/cancers13143416/). Collectively, these findings underscore the importance of studying tumor biology and stem cells in developing effective therapeutic strategies for GBM.

The identification of diagnostic and prognostic biomarkers in glioblastoma (GBM) is crucial for improving patient management and treatment outcomes. Recent studies have focused on the role of methylthioadenosine phosphorylase (MTAP) deletion as a potential biomarker, although findings indicate that homozygous MTAP deletion does not correlate with elevated levels of its substrate, methylthioadenosine, challenging previous assumptions about its role in GBM (ref: Barekatain doi.org/10.1038/s41467-021-24240-3/). Additionally, the delivery of exosomal miR-1246 from glioma patient body fluids has been shown to drive the differentiation and activation of myeloid-derived suppressor cells, contributing to the immunosuppressive microenvironment of GBM (ref: Qiu doi.org/10.1016/j.ymthe.2021.06.023/). This highlights the potential of exosomal miRNAs as biomarkers for monitoring tumor progression and therapeutic responses. Furthermore, the use of optical tissue clearing and machine learning techniques has enabled precise characterization of drug accumulation in brain tumors, providing valuable insights into the pharmacokinetics of therapeutic agents (ref: Kostrikov doi.org/10.1038/s42003-021-02275-y/). These advancements in biomarker discovery and diagnostic techniques are essential for enhancing the management of GBM patients.