The tumor microenvironment (TME) plays a crucial role in glioblastoma (GBM) progression and treatment resistance. A study by Zheng et al. identified Nestin+/CD31+ cells within the hypoxic perivascular niche as key regulators of chemoresistance in GBM, demonstrating that these cells, rather than pericytes, correlate with poor patient prognosis (ref: Zheng doi.org/10.1093/neuonc/). Yi et al. further explored the metabolic pathways in GBM, revealing that PTRF/cavin-1 enhances tumor proliferation while suppressing immune responses through a cPLA2-mediated phospholipid remodeling pathway (ref: Yi doi.org/10.1093/neuonc/). Additionally, Sahebjam et al. investigated the combination of hypofractionated stereotactic re-irradiation with pembrolizumab and bevacizumab, finding promising safety and preliminary efficacy in recurrent high-grade gliomas (ref: Sahebjam doi.org/10.1093/neuonc/). These studies collectively highlight the complex interplay between tumor cells and the immune microenvironment, emphasizing the need for innovative therapeutic strategies that target these interactions. The immunological classification of gliomas by Feng et al. further supports this notion, showing that higher tumor immunity correlates with increased genomic instability and poor prognosis (ref: Feng doi.org/10.1186/s12974-020-02030-w/).

Molecular characterization of glioblastomas has revealed significant insights into their heterogeneity and potential therapeutic targets. Dejaegher et al. demonstrated that DNA methylation-based subclassification correlates with T-cell infiltration and patient survival, suggesting that epigenetic profiles can inform treatment strategies (ref: Dejaegher doi.org/10.1093/neuonc/). Ji et al. proposed tailored radiological assessment schedules for high-grade glioma patients based on IDH mutation status, optimizing follow-up care (ref: Ji doi.org/10.1093/neuonc/). Vigneswaran et al. identified YAP/TAZ transcriptional coactivators as therapeutic vulnerabilities in EGFR-mutant glioblastomas, where their inhibition led to reduced cell proliferation and increased apoptosis (ref: Vigneswaran doi.org/10.1158/1078-0432.CCR-20-0018/). Stasik et al. highlighted the frequent genomic loss of TET1 in IDH-wild-type glioblastomas, linking it to poor survival outcomes, while Suwala et al. characterized a distinct type of IDH-mutant astrocytoma with mismatch repair deficiency, underscoring the importance of genetic alterations in prognosis (ref: Stasik doi.org/10.1016/j.neo.2020.10.010/; Suwala doi.org/10.1007/s00401-020-02243-6/).

Innovative therapeutic strategies and drug delivery methods are essential for improving glioblastoma treatment outcomes. Jacob et al. described the generation of patient-derived glioblastoma organoids, which preserve tumor heterogeneity and can be utilized for CAR T cell testing, providing a more representative model for therapeutic evaluation (ref: Jacob doi.org/10.1038/s41596-020-0402-9/). Gregory et al. engineered synthetic protein nanoparticles to enhance drug delivery across the blood-brain barrier, addressing a significant challenge in glioblastoma therapy (ref: Gregory doi.org/10.1038/s41467-020-19225-7/). Fan et al. developed chimaeric polypeptide polymersomes for targeted delivery of Plk1 inhibitors, demonstrating improved therapeutic efficacy in orthotopic glioblastoma models (ref: Fan doi.org/10.1016/j.jconrel.2020.10.043/). Lee et al. showcased the potential of ECO/siRNA nanoparticles to enhance radiation response by targeting DNA damage repair mechanisms, highlighting a promising avenue for radiosensitization (ref: Lee doi.org/10.3390/cancers12113260/). Dey et al. explored the combination of atypical PKC signaling interruption with Temozolomide, revealing synergistic effects that significantly reduced glioblastoma cell viability (ref: Dey doi.org/10.1016/j.cellsig.2020.109819/).

Genetic and epigenetic alterations are pivotal in understanding glioblastoma pathogenesis and treatment resistance. Stasik et al. reported frequent bi-allelic deletions of TET1 in IDH-wild-type glioblastomas, which co-occurred with EGFR amplification and were associated with poor survival outcomes, indicating a potential target for therapeutic intervention (ref: Stasik doi.org/10.1016/j.neo.2020.10.010/). Suwala et al. identified a novel epigenetic group of IDH-mutant astrocytomas with mismatch repair deficiency, suggesting that these tumors may require different therapeutic strategies compared to their IDH-wild counterparts (ref: Suwala doi.org/10.1007/s00401-020-02243-6/). Yi et al. highlighted the role of PTRF/cavin-1 in remodeling phospholipid metabolism, which not only promotes tumor proliferation but also suppresses immune responses, further complicating the treatment landscape (ref: Yi doi.org/10.1093/neuonc/). The interplay between genetic alterations and therapeutic responses underscores the necessity for personalized treatment approaches based on molecular profiling.

Clinical outcomes in glioblastoma are influenced by various prognostic factors and treatment strategies. Truong et al. developed a deep learning method for visualizing tumor heterogeneity and grading through digital pathology, which may enhance clinical decision-making and patient management (ref: Truong doi.org/10.1093/noajnl/). Korshoej et al. conducted a phase I trial assessing the safety and feasibility of skull remodeling surgery to enhance tumor treating fields therapy, indicating a novel approach to improve treatment efficacy in recurrent glioblastoma (ref: Korshoej doi.org/10.1093/noajnl/). Kassubek et al. emphasized the role of advanced MRI techniques in supporting clinical drug development for malignant glioma, highlighting the need for improved biomarkers to monitor treatment response (ref: Kassubek doi.org/10.1016/j.drudis.2020.11.023/). Bhavya et al. investigated the multifaceted role of MTH1 in glioma, linking its expression to DNA damage and apoptosis, which could inform future therapeutic strategies (ref: Bhavya doi.org/10.1016/j.lfs.2020.118673/).

Innovative imaging and monitoring techniques are crucial for enhancing glioblastoma management. Zheng et al. utilized a hypoxic chamber and 3D microfluidic chips to simulate the hypoxic perivascular niche, providing insights into the tumor microenvironment's role in chemoresistance (ref: Zheng doi.org/10.1093/neuonc/). Hara et al. explored the expression of CD1d in glioblastoma as a target for NKT cell-based immunotherapy, demonstrating the potential for harnessing the immune system in treatment strategies (ref: Hara doi.org/10.1007/s00262-020-02742-1/). Kim et al. focused on PARK7's role in maintaining glioblastoma stem cell stemness, suggesting that targeting this pathway could enhance treatment efficacy (ref: Kim doi.org/10.1038/s41388-020-01543-1/). Lee et al. demonstrated the effectiveness of ECO/siRNA nanoparticles in targeting DNA damage repair, showcasing a novel approach to improve radiation therapy outcomes (ref: Lee doi.org/10.3390/cancers12113260/). Muglia et al. identified temporal muscle thickness as a potential prognostic marker for sarcopenia in glioblastoma patients, indicating the importance of monitoring physical health in treatment planning (ref: Muglia doi.org/10.1007/s00330-020-07471-8/).

The role of stem cells and tumor heterogeneity in glioblastoma is critical for understanding treatment resistance and disease progression. Jacob et al. highlighted the generation of patient-derived glioblastoma organoids, which maintain the cellular and mutational diversity of tumors, facilitating CAR T cell testing and personalized therapy development (ref: Jacob doi.org/10.1038/s41596-020-0402-9/). Nayak et al. conducted a phase II study comparing pembrolizumab alone versus in combination with bevacizumab in recurrent glioblastoma, revealing limited benefits but emphasizing the need for innovative approaches in treatment (ref: Nayak doi.org/10.1158/1078-0432.CCR-20-2500/). Pinto et al. discovered that glioblastoma stem cells transfer mitochondria through tunneling nanotubes, contributing to tumor networking and therapy resistance, which underscores the complexity of intercellular communication in glioblastoma (ref: Pinto doi.org/10.1042/BCJ20200710/). Iorgulescu et al. evaluated the impact of concurrent dexamethasone on the efficacy of immune checkpoint blockade, finding that it limits clinical benefits, thus highlighting the importance of managing treatment regimens (ref: Iorgulescu doi.org/10.1158/1078-0432.CCR-20-2291/). Bhavya et al. also noted the increased expression of MTH1 in glioma tissues, linking it to various cellular processes, which may inform future therapeutic strategies (ref: Bhavya doi.org/10.1016/j.lfs.2020.118673/).