The interactions between glioblastoma cells and the tumor microenvironment play a crucial role in tumor progression and therapeutic resistance. Hara et al. utilized single-cell RNA sequencing to demonstrate that macrophages can induce a transition of glioblastoma cells into mesenchymal-like states, which are associated with increased invasiveness and resistance to therapy (ref: Hara doi.org/10.1016/j.ccell.2021.05.002/). This finding highlights the importance of immune cell interactions in shaping tumor behavior. Huang et al. further explored the role of mitochondrial reactive oxygen species (ROS) in glioma stem-like cells, revealing that prohibitin regulates ROS levels and contributes to therapeutic resistance, indicating a potential target for enhancing treatment efficacy (ref: Huang doi.org/10.1038/s41467-021-24108-6/). Additionally, Fidanza et al. proposed a novel approach to enhance peptide vaccine efficacy by improving proteasomal processing, which could augment immune responses against glioblastoma (ref: Fidanza doi.org/10.1126/scitranslmed.aax4100/). These studies collectively underscore the complex interplay between glioblastoma cells and their microenvironment, suggesting that targeting these interactions may improve therapeutic outcomes.

Genomic and epigenetic alterations are pivotal in glioblastoma pathogenesis and prognosis. Stępniak et al. mapped chromatin accessibility and identified active regulatory elements that contribute to glioma development, emphasizing the role of epigenetic modifications in gene expression regulation (ref: Stępniak doi.org/10.1038/s41467-021-23922-2/). Fujimoto et al. highlighted the significance of TERT promoter mutations as a diagnostic criterion for IDH-wildtype diffuse astrocytic gliomas, demonstrating that these mutations are associated with poor prognosis (ref: Fujimoto doi.org/10.1007/s00401-021-02337-9/). Furthermore, Rousso-Noori et al. investigated the potential of CAR T cells targeting P32, revealing their dual therapeutic potential against gliomas, which may be influenced by the tumor's genomic landscape (ref: Rousso-Noori doi.org/10.1038/s41467-021-23817-2/). These findings illustrate the critical role of genomic and epigenetic factors in glioblastoma, providing insights into potential biomarkers and therapeutic targets.

Therapeutic strategies for glioblastoma continue to evolve, focusing on overcoming drug resistance. Huang et al. demonstrated that prohibitin plays a significant role in maintaining low ROS levels in glioma stem-like cells, which contributes to their resistance to therapies (ref: Huang doi.org/10.1038/s41467-021-24108-6/). This suggests that targeting prohibitin could enhance the effectiveness of existing treatments. Yun et al. evaluated the radiosensitizing effects of AZD0530, a Src kinase inhibitor, showing that it enhances the radiosensitivity of glioblastoma cells and stem-like cells, indicating a promising combinatorial approach to therapy (ref: Yun doi.org/10.1158/1535-7163.MCT-20-0883/). Additionally, the study by Kawabata et al. on accelerator-based boron neutron capture therapy (BNCT) provided evidence for its safety and efficacy in recurrent glioblastoma, further expanding the therapeutic arsenal against this challenging malignancy (ref: Kawabata doi.org/10.1093/noajnl/). Collectively, these studies highlight the ongoing efforts to develop innovative therapeutic strategies that address the complexities of glioblastoma treatment.

Advancements in imaging and diagnostic approaches are crucial for improving glioblastoma management. Chen et al. developed ultrasmall nanoparticles for NIR-II fluorescence imaging, enhancing the ability to visualize glioblastoma in vivo, which could significantly improve surgical outcomes (ref: Chen doi.org/10.1016/j.biomaterials.2021.120916/). Talati et al. utilized MR spectroscopic imaging to predict responses to anti-angiogenic therapy in recurrent glioblastoma, demonstrating that metabolic changes can serve as early indicators of treatment efficacy (ref: Talati doi.org/10.1093/noajnl/). Furthermore, Islam et al. proposed a radiogenomic approach for survival prediction in glioblastoma, integrating MRI features with gene expression data, which could refine prognostic assessments and treatment planning (ref: Islam doi.org/10.1016/j.compmedimag.2021.101906/). These innovations in imaging and diagnostics are essential for enhancing the precision of glioblastoma treatment and monitoring.

Understanding the cellular and molecular mechanisms underlying glioblastoma is vital for developing targeted therapies. Huang et al. identified that prohibitin regulates mitochondrial ROS in glioma stem-like cells, linking metabolic regulation to therapeutic resistance (ref: Huang doi.org/10.1038/s41467-021-24108-6/). This finding suggests that metabolic pathways could be potential therapeutic targets. The study by Rousso-Noori et al. on CAR T cells targeting P32 highlighted the challenges posed by tumor heterogeneity and antigen loss, emphasizing the need for innovative strategies to enhance the effectiveness of immunotherapy in glioblastoma (ref: Rousso-Noori doi.org/10.1038/s41467-021-23817-2/). Zhou et al. explored the role of circMELK in promoting glioblastoma cell tumorigenesis through the miR-593/EphB2 axis, providing insights into the regulatory networks that govern glioblastoma progression (ref: Zhou doi.org/10.1016/j.omtn.2021.05.002/). These studies collectively enhance our understanding of the complex biological mechanisms driving glioblastoma and inform the development of novel therapeutic strategies.

Patient-derived models are essential for preclinical studies in glioblastoma research. Eckel-Passow et al. emphasized the importance of experimental design in patient-derived xenograft (PDX) studies, demonstrating that using multiple PDX lines can significantly enhance statistical power in detecting treatment effects (ref: Eckel-Passow doi.org/10.1093/neuonc/). This approach is crucial for accurately translating preclinical findings to clinical settings. Huang et al. also contributed to this theme by revealing how prohibitin influences glioma stem-like cell behavior, which could be modeled in PDX systems to better understand therapeutic responses (ref: Huang doi.org/10.1038/s41467-021-24108-6/). Additionally, Cai et al. developed a noninvasive diagnostic approach based on 5-hydroxymethylcytosines in circulating cell-free DNA, which could enhance early detection of gliomas and inform treatment decisions (ref: Cai doi.org/10.1093/noajnl/). These studies highlight the significance of patient-derived models in advancing glioblastoma research and improving clinical outcomes.

Clinical outcomes in glioblastoma are influenced by various prognostic factors. Khasraw et al. reported on the efficacy of bintrafusp alfa in recurrent glioblastoma, revealing median overall survival rates and progression-free survival metrics that underscore the challenges in treating this aggressive cancer (ref: Khasraw doi.org/10.1093/noajnl/). The study by Islam et al. introduced a radiogenomic survival prediction model that integrates MRI features with gene expression data, potentially offering a more accurate prognostic tool for glioblastoma patients (ref: Islam doi.org/10.1016/j.compmedimag.2021.101906/). Furthermore, the preparation of 3D human glioblastoma spheroids by Bae et al. provides a more physiologically relevant model for studying tumor behavior and treatment responses, which could lead to better prognostic assessments (ref: Bae doi.org/10.1016/j.ijbiomac.2021.06.083/). These findings collectively emphasize the need for comprehensive approaches to understanding clinical outcomes and prognostic factors in glioblastoma.

The exploration of novel therapeutic agents and combinations is critical in the fight against glioblastoma. Huang et al. highlighted the role of prohibitin in regulating ROS levels in glioma stem-like cells, suggesting that targeting this pathway could enhance treatment responses (ref: Huang doi.org/10.1038/s41467-021-24108-6/). Additionally, Yun et al. demonstrated that AZD0530, a Src kinase inhibitor, can enhance the radiosensitivity of glioblastoma cells, indicating its potential as a combinatorial agent in therapy (ref: Yun doi.org/10.1158/1535-7163.MCT-20-0883/). The study by Kawabata et al. on accelerator-based BNCT provided promising results for recurrent glioblastoma, showcasing its safety and efficacy as a novel treatment modality (ref: Kawabata doi.org/10.1093/noajnl/). These studies reflect the ongoing efforts to identify and develop innovative therapeutic strategies that can improve outcomes for glioblastoma patients.