The immunotherapy landscape for glioblastoma (GBM) is evolving, with recent studies highlighting the challenges posed by the immunosuppressive tumor microenvironment (TME). One study introduced survivin peptide-CpG oligodeoxynucleotide nanovaccines (SPOD-NV), which were administered intranasally and intravenously, demonstrating a robust immune response against murine GBM (ref: Shi doi.org/10.1002/adma.202420630/). Another significant contribution is the establishment of Glioportal, a comprehensive biobank that integrates multi-omics data to elucidate the molecular heterogeneity and cellular plasticity of GBM, providing a resource for precision therapies (ref: Pang doi.org/10.1093/neuonc/). Furthermore, research has identified cancer-associated fibroblasts (CAFs) as key players in modulating the TME, particularly through the expression of LRRC15, which limits the efficacy of PD-1 immunotherapy (ref: Luo doi.org/10.1093/neuonc/). This highlights the need for strategies that can reprogram the TME to enhance immunotherapeutic outcomes. In addition to CAFs, the role of specific genetic alterations in immune evasion has been explored. For instance, the EGFRvIII mutation in GBM cells has been shown to drive macrophage polarization towards an immunosuppressive phenotype, further complicating therapeutic interventions (ref: Yuan doi.org/10.1038/s41419-025-07771-1/). The integration of spatial transcriptomics and single-cell RNA sequencing has provided insights into the spatial organization of tumor heterogeneity, revealing the presence of extrachromosomal DNA and loss of heterozygosity in gliomas (ref: Webb doi.org/10.1038/s41467-025-59805-z/). Collectively, these studies underscore the complexity of the immune landscape in GBM and the necessity for innovative approaches to overcome the barriers posed by the TME.

Targeted therapies for glioblastoma (GBM) are increasingly focusing on overcoming drug resistance mechanisms that hinder treatment efficacy. A phase 1 trial investigated the use of bivalent CAR T cells targeting EGFR and IL-13Rα2, demonstrating potential in recurrent GBM patients, with a median overall survival of 12-15 months (ref: Bagley doi.org/10.1038/s41591-025-03745-0/). This approach highlights the promise of CAR T cell therapy in addressing the challenges of tumor heterogeneity and antigen escape. Additionally, novel GABAAR antagonists have been identified that target gene hubs in high-grade gliomas, suggesting a new avenue for therapeutic intervention (ref: Shard doi.org/10.1093/neuonc/). Moreover, the development of a metal-phenolic network nanoresensitizer has shown efficacy in overcoming Temozolomide resistance by targeting drug-tolerant cells through metabolic adaptation strategies (ref: Yin doi.org/10.1021/acs.nanolett.5c01141/). This innovative approach is complemented by the introduction of near-infrared II (NIR-II) engineered exosome nanotheranostic probes, which enhance tumor targeting and penetration, thereby improving treatment outcomes (ref: Yu doi.org/10.1021/acsnano.5c01541/). The integration of these targeted therapies with advanced imaging techniques has also been explored, with a three-step-guided prediction method for GBM recurrence showing promising results in improving predictive accuracy (ref: Zhao doi.org/10.1016/j.compmedimag.2025.102585/). Together, these studies emphasize the need for multifaceted strategies to combat drug resistance and improve therapeutic efficacy in GBM.

The tumor microenvironment (TME) plays a critical role in glioblastoma (GBM) progression and therapeutic resistance. Recent research has focused on the impact of nuclear cholesterol on cancer stem cells, revealing that alterations in nuclear size and DNA damage responses are influenced by cholesterol levels, which may contribute to malignancy (ref: Duan doi.org/10.1093/neuonc/). Additionally, a novel 3D brain vascular niche model has been developed to study GBM infiltration and dormancy, successfully recapitulating key features of tumor heterogeneity and vascular association (ref: Lee doi.org/10.1002/advs.202500689/). This model provides a more physiologically relevant platform for understanding GBM behavior in the context of the TME. The extracellular matrix (ECM) has also been characterized in high-grade gliomas, revealing its significant role in tumor progression and immune evasion (ref: Day doi.org/10.1038/s41698-025-00956-z/). Furthermore, metabolic adaptations in GBM cells, such as fructolysis under glucose deprivation, have been linked to enhanced survival, indicating that metabolic plasticity is a key factor in tumor resilience (ref: Li doi.org/10.1038/s41420-025-02544-3/). These findings highlight the intricate interplay between the TME and metabolic pathways, suggesting that targeting metabolic adaptations may provide new therapeutic opportunities in GBM treatment.

Molecular mechanisms underlying glioblastoma (GBM) pathogenesis are being elucidated, with a focus on identifying biomarkers for prognosis and therapeutic targets. The utilization of universal-targeting mSA2 CAR-T cells represents a novel approach to circumvent tumor heterogeneity and antigen escape, potentially enhancing the efficacy of CAR-T cell therapies in GBM (ref: Kourtesakis doi.org/10.1080/2162402X.2025.2518631/). Additionally, the role of melatonin in inhibiting tumor growth through modulation of circadian rhythm and angiogenesis-related genes has been highlighted, suggesting its potential as an adjunct therapy (ref: Cardenas-Romero doi.org/10.1111/jpi.70064/). Gasdermin E has emerged as a critical factor in GBM, exhibiting pyroptosis resistance and tumor-promoting functions, which complicates treatment strategies (ref: Solel doi.org/10.1038/s41420-025-02572-z/). Furthermore, RIPK1 expression has been linked to poor survival outcomes in diffuse gliomas, indicating its potential as a prognostic marker and therapeutic target (ref: Amorós Morales doi.org/10.3390/ijms26125555/). The circadian rhythm gene network has also been shown to distinguish molecular profiles and prognoses in GBM patients, providing a framework for personalized treatment approaches (ref: Wan doi.org/10.3390/ijms26125873/). Collectively, these studies underscore the importance of understanding molecular mechanisms and identifying biomarkers to improve therapeutic strategies in GBM.

Innovative therapeutic approaches for glioblastoma (GBM) are being developed to enhance treatment efficacy and overcome existing barriers. A self-directed Trojanbot-enzymatic nanobot has been designed for targeted therapy, addressing the challenges posed by the blood-brain barrier (BBB) and the tumor microenvironment (TME) (ref: Gao doi.org/10.1038/s41467-025-60422-z/). This dual-functionality aims to improve drug delivery and penetration into GBM tissues, representing a significant advancement in nanotechnology applications for cancer treatment. Additionally, transcriptome-wide analyses have been conducted to explore the origins of brain cancer, emphasizing the need for models that accurately reflect the complexity of gliomas (ref: Paglia doi.org/10.3390/ijms26115115/). Moreover, advanced imaging techniques have been utilized to differentiate between various intracranial tumors, including GBM, using multiparametric diffusion imaging (ref: Würtemberger doi.org/10.1093/noajnl/). This approach enhances diagnostic accuracy and may inform treatment decisions. The integration of dual-plasma discharge tubes for synergistic GBM treatment has also shown promise, amplifying anti-tumor effects without causing thermal injury (ref: Murphy doi.org/10.3390/cancers17122036/). These novel strategies highlight the ongoing efforts to innovate therapeutic modalities and improve outcomes for patients with GBM.

Recent genomic and transcriptomic studies have provided valuable insights into the molecular landscape of glioblastoma (GBM). The establishment of Glioportal, a comprehensive biobank, has facilitated the exploration of ligand-mediated mesenchymal transition and the inherent molecular heterogeneity of GBM (ref: Pang doi.org/10.1093/neuonc/). This resource is pivotal for advancing precision therapies and understanding the complex interactions within the tumor microenvironment. Additionally, the characterization of the extracellular matrix (ECM) in high-grade gliomas has revealed its critical role in tumor progression and immune evasion, underscoring the need for targeted immunotherapy approaches (ref: Day doi.org/10.1038/s41698-025-00956-z/). Furthermore, the identification of biomarkers such as RIPK1 has been linked to prognosis in diffuse gliomas, while the circadian rhythm gene network has shown potential in distinguishing molecular profiles and predicting patient outcomes (ref: Wan doi.org/10.3390/ijms26125873/). These findings emphasize the importance of integrating genomic and transcriptomic data to inform therapeutic strategies and improve patient management in GBM. Collectively, these studies highlight the dynamic interplay between genetic alterations and the tumor microenvironment, paving the way for novel therapeutic interventions.