Oncolytic virus therapy has emerged as a promising approach for treating glioblastoma, particularly with the use of G47Δ, a triple-mutated oncolytic herpes simplex virus type 1. A phase 2 trial involving 19 patients with residual or recurrent glioblastoma demonstrated an impressive 1-year survival rate of 84.2% after treatment with G47Δ, highlighting its potential efficacy in this challenging patient population (ref: Todo doi.org/10.1038/s41591-022-01897-x/). Additionally, a phase I/II study further confirmed the safety profile of G47Δ, with intratumoral administration showing promise for patients who had previously undergone radiation and temozolomide therapies (ref: Todo doi.org/10.1038/s41467-022-31262-y/). These findings suggest that G47Δ could be a viable option for patients with progressive glioblastoma, although further studies are necessary to establish long-term outcomes and optimal treatment regimens. In contrast, the phase III trial of depatuxizumab mafodotin, targeting EGFR amplification, revealed no significant overall survival benefit compared to placebo, despite a longer progression-free survival in certain subgroups (ref: Lassman doi.org/10.1093/neuonc/). This discrepancy underscores the complexity of glioblastoma treatment and the need for personalized approaches based on tumor genetics.

Recent studies have elucidated various molecular mechanisms and potential biomarkers in glioblastoma, focusing on the roles of specific genes and pathways. The identification of ELF4 as a critical component of a miRNA-transcription factor network suggests its involvement in glioblastoma's undifferentiated state, with implications for receptor signaling and lipid dynamics (ref: Kosti doi.org/10.1093/neuonc/). Furthermore, the discovery of 249C as a selective cytotoxic agent against Ras-mutant cancers highlights the potential for targeting V-type ATPases to inhibit autophagy and macropinocytosis, which are crucial for the survival of Ras-driven tumors (ref: Tolani doi.org/10.1038/s41587-022-01386-z/). Additionally, the development of a gene expression signature related to brain radiotoxicity has been linked to survival prognosis in glioblastoma patients, indicating that molecular profiling could guide therapeutic strategies (ref: Reyes-González doi.org/10.1093/neuonc/). The integration of these findings into clinical practice may enhance the precision of glioblastoma management, although further validation is required.

The tumor microenvironment (TME) in glioblastoma presents significant challenges for effective immunotherapy, characterized by its immunosuppressive nature. A novel approach utilizing targeted inducible delivery of immunoactivating cytokines, such as interferon-α and interleukin-12, has shown promise in reprogramming the TME and inhibiting tumor growth in mouse models (ref: Birocchi doi.org/10.1126/scitranslmed.abl4106/). This strategy aims to mitigate the toxic effects associated with systemic administration of these cytokines by delivering them directly to the tumor site. Additionally, the role of tumor-associated astrocytes in regulating the immunometabolic landscape of glioblastoma has been highlighted, suggesting that targeting these cells may provide a new therapeutic avenue (ref: Perelroizen doi.org/10.1093/brain/). Moreover, the exploration of glioblastoma-associated natural killer cell extracellular vesicles as a noninvasive diagnostic tool underscores the potential for liquid biopsies in monitoring tumor dynamics and immune checkpoint expression (ref: Ishwar doi.org/10.1021/acsnano.2c03055/). Collectively, these studies emphasize the need for innovative strategies to overcome TME barriers and enhance the efficacy of immunotherapies in glioblastoma.

Genetic and epigenetic factors play a crucial role in the pathogenesis and treatment response of glioblastoma. Recent research has demonstrated that DNA methylation subclasses can predict the benefit from gross total tumor resection in IDH-wildtype glioblastoma patients, indicating that molecular characteristics may guide surgical decision-making (ref: Drexler doi.org/10.1093/neuonc/). Additionally, the identification of specific mutations, such as those in the Ras family, has been linked to sensitivity to targeted therapies, highlighting the importance of genetic profiling in treatment planning (ref: Tolani doi.org/10.1038/s41587-022-01386-z/). The interplay between genetic alterations and the tumor microenvironment further complicates the landscape of glioblastoma, as evidenced by the differential expression of immune checkpoint proteins in glioblastoma-associated extracellular vesicles (ref: Ishwar doi.org/10.1021/acsnano.2c03055/). These findings suggest that a comprehensive understanding of genetic and epigenetic factors is essential for developing personalized therapeutic strategies and improving patient outcomes.

Drug resistance remains a significant hurdle in the treatment of glioblastoma, with various mechanisms contributing to therapeutic failure. The phase III trial of depatuxizumab mafodotin revealed no overall survival benefit despite improved progression-free survival in certain subgroups, emphasizing the complexity of resistance mechanisms in glioblastoma (ref: Lassman doi.org/10.1093/neuonc/). Furthermore, the identification of 249C as a selective agent against Ras-mutant cancers suggests that targeting specific pathways may help overcome resistance, particularly in tumors reliant on autophagy and macropinocytosis for survival (ref: Tolani doi.org/10.1038/s41587-022-01386-z/). Additionally, the exploration of glioblastoma-associated extracellular vesicles as potential biomarkers for drug response highlights the need for innovative approaches to monitor and predict resistance (ref: Ishwar doi.org/10.1021/acsnano.2c03055/). Understanding the underlying mechanisms of drug resistance is critical for developing effective treatment strategies and improving patient outcomes in glioblastoma.

Tumor invasion and metastasis are critical aspects of glioblastoma pathology, with recent studies shedding light on the molecular mechanisms involved. The role of ELF4 in regulating glioblastoma receptor signaling and lipid dynamics suggests that it may serve as a bridge between various signaling pathways that promote tumor invasion (ref: Kosti doi.org/10.1093/neuonc/). Additionally, the sensitivity of Ras-mutant cancers to small molecule inhibitors of V-type ATPases indicates a potential therapeutic target for preventing invasion and metastasis, as these pathways are crucial for tumor cell survival and proliferation (ref: Tolani doi.org/10.1038/s41587-022-01386-z/). The immunosuppressive nature of the glioblastoma microenvironment further complicates invasion dynamics, as evidenced by the targeted delivery of immunoactivating cytokines to reprogram the TME and inhibit tumor growth (ref: Birocchi doi.org/10.1126/scitranslmed.abl4106/). These findings underscore the need for a multifaceted approach to address the challenges of tumor invasion and metastasis in glioblastoma.

Clinical trials play a pivotal role in advancing glioblastoma treatment, with recent studies providing valuable insights into treatment outcomes. The phase 2 trial of G47Δ demonstrated a remarkable 1-year survival rate of 84.2% in patients with residual or recurrent glioblastoma, showcasing the potential of oncolytic virus therapy (ref: Todo doi.org/10.1038/s41591-022-01897-x/). In contrast, the phase III trial of depatuxizumab mafodotin revealed no significant overall survival benefit compared to placebo, despite improved progression-free survival in specific subgroups, highlighting the complexity of treatment responses in glioblastoma (ref: Lassman doi.org/10.1093/neuonc/). Furthermore, the exploration of glioblastoma-associated natural killer cell extracellular vesicles as a noninvasive diagnostic tool emphasizes the potential for liquid biopsies in monitoring treatment outcomes and guiding therapeutic decisions (ref: Ishwar doi.org/10.1021/acsnano.2c03055/). These findings underscore the importance of ongoing clinical research to refine treatment strategies and improve patient outcomes in glioblastoma.