Recent advancements in targeted therapies and drug delivery systems for glioblastoma (GBM) have shown promising results in enhancing treatment efficacy. One study demonstrated that avapritinib, a PDGFRA inhibitor, is well tolerated and resulted in radiographic responses in 3 out of 7 patients with PDGFRA-altered high-grade glioma, indicating its potential role in targeted therapy (ref: Mayr doi.org/10.1016/j.ccell.2025.02.018/). Another innovative approach involved engineered bacterial outer membrane vesicles (OMVs) for co-delivery of doxorubicin and CD47-siRNA, which effectively overcame immune resistance in GBM, showcasing the multifunctional properties of OMVs as carriers and immune adjuvants (ref: You doi.org/10.1002/adma.202418053/). Additionally, self-oxygenating PROTAC microneedles have been engineered to enhance glioblastoma therapy by enabling spatiotemporally confined protein degradation, addressing the challenges posed by the blood-brain barrier (BBB) (ref: Jiang doi.org/10.1002/adma.202411869/). Moreover, convection-enhanced delivery (CED) of drug-loaded nanoparticles has been explored to improve therapeutic targeting and prolong drug residence time in brain tumor tissues, which is critical given the rapid clearance of free drugs (ref: Pickering doi.org/10.1021/jacs.4c16898/). A phase 2 study on multiparametric MRI-guided high-dose radiation therapy combined with temozolomide indicated that individualized, response-adaptive radiation therapy is feasible and may improve outcomes for newly diagnosed GBM patients (ref: Kim doi.org/10.1016/j.ijrobp.2025.02.020/). Furthermore, disulfiram-loaded electrospun fibers have been developed for controlled release in the postsurgical cavity, demonstrating antimicrobial and antitumoral properties (ref: Gonzalez-Prada doi.org/10.1016/j.jconrel.2025.113615/). Self-assembled genistein nanoparticles were also found to suppress epithelial-mesenchymal transition in GBM by targeting MMP9, highlighting the importance of molecular targeting in treatment strategies (ref: Zhao doi.org/10.1016/j.mtbio.2025.101606/).

The tumor microenvironment (TME) plays a crucial role in glioblastoma progression and response to therapy. A comprehensive single-cell atlas of endothelial and mural cells across primary and metastatic brain tumors revealed significant alterations in the blood-brain barrier (BBB) components, which are critical for understanding tumor behavior and therapeutic resistance (ref: Bejarano doi.org/10.1016/j.immuni.2025.02.022/). In another study, blocking ITGA5 was shown to enhance the efficacy of anti-PD-1 therapy by remodeling tumor-associated macrophages, indicating the potential for targeting specific immune cell interactions to improve immunotherapy outcomes (ref: Zhao doi.org/10.1002/cac2.70016/). Additionally, the activation of antiviral immune responses through viral mimicry has been demonstrated to potentiate immune checkpoint inhibition in GBM models, suggesting that manipulating innate immune pathways could enhance therapeutic efficacy (ref: Seetharam doi.org/10.1172/JCI183745/). Multi-omics analyses have identified dependencies on specific epigenetic modifications, such as H3K9me3 methyltransferase activity, which correlate with reduced immune responses and increased tumor proliferation (ref: Xie doi.org/10.1038/s41698-025-00829-5/). Furthermore, a lupus-derived autoantibody that binds to intracellular RNA was found to activate cGAS-mediated tumor immunity, promoting survival in glioblastoma models, thus highlighting novel avenues for immune modulation (ref: Chen doi.org/10.1126/scisignal.adk3320/). Lastly, an acidity-triggered bioorthogonal assembly nanoplatform was developed to enhance glioblastoma immunotherapy by targeting both CXCL12/CXCR4 and adenosine-A2AR pathways, demonstrating the importance of dual-regulation strategies in overcoming TME-induced immunosuppression (ref: Wei doi.org/10.1016/j.biomaterials.2025.123216/).

Understanding the genetic and molecular mechanisms underlying glioblastoma is essential for developing targeted therapies. Recent research has highlighted the role of three-dimensional regulatory hubs in supporting oncogenic programs in glioblastoma, where hyperconnected enhancer-promoter networks were identified in patient-derived glioblastoma stem cells, correlating with high expression of oncogenic genes (ref: Breves doi.org/10.1016/j.molcel.2025.03.007/). Additionally, the dual role of WNT10A was investigated, revealing its involvement in promoting glioblastoma malignancy while also remodeling the tumor microenvironment through activation of the PI3K-AKT pathway in tumor-associated macrophages (ref: Xue doi.org/10.1093/neuonc/). Another study identified Centromere protein U (CENPU) as a key mediator of temozolomide resistance in glioblastoma, where its downregulation enhanced sensitivity to treatment by affecting DNA damage repair mechanisms (ref: Sun doi.org/10.1016/j.drup.2025.101214/). Moreover, targeting the PDGFRA-SHP2 signaling pathway was shown to enhance radiotherapy effectiveness in IDH1-mutant gliomas, indicating the distinct molecular characteristics of different glioma subtypes (ref: Yu doi.org/10.1093/neuonc/). The dependency on H3K9me3 methyltransferase activity was further confirmed through multi-omics analysis, linking it to reduced immune responses and increased tumor proliferation (ref: Xie doi.org/10.1038/s41698-025-00829-5/). Lastly, the oncogenic role of SLC25A13 was unveiled through a pan-cancer analysis, revealing its impact on glioma progression and suggesting its potential as a therapeutic target (ref: Wu doi.org/10.1186/s12935-025-03696-z/).

Immunotherapy and combination treatments are emerging as promising strategies for glioblastoma management. A multi-institutional phase 1 clinical trial explored the safety of combining surgical upfront immunotherapy with aglatimagene besadenovec, followed by chemoradiation and adjuvant nivolumab for newly diagnosed glioblastoma patients, aiming to assess immune activation metrics that correlate with clinical outcomes (ref: Wen doi.org/10.1093/neuonc/). Another innovative approach involved leveraging SARS-CoV-2-specific immunity through lipid nanoparticle (LNP)-RNA-mediated antigen presentation, redirecting T-cell responses against cancer (ref: Xue doi.org/10.1038/s41467-025-57149-2/). CAR-NK cell therapy combined with checkpoint inhibition was also shown to induce an NKT cell response, effectively reversing the immunosuppressive tumor microenvironment in glioblastoma (ref: Strassheimer doi.org/10.1038/s41416-025-02977-8/). Moreover, a structurally modified sinomenine demonstrated dual anti-GBM effects by inhibiting glioblastoma proliferation and inducing necroptosis, which further mediates lysosomal cell death, highlighting the potential of natural compounds in glioblastoma therapy (ref: Yang doi.org/10.1111/bph.17464/). The identification of a novel target, the prostaglandin F2 receptor negative regulator, for CAR-T cell therapy also presents a promising avenue for glioblastoma treatment (ref: Kuroda doi.org/10.1007/s00262-025-03979-4/). Additionally, granulocyte-macrophage colony-stimulating factor (GM-CSF) was evaluated in combination with hypofractionated intensity-modulated radiation therapy and temozolomide, showing a 6-month progression-free survival rate of 68.3% in newly diagnosed glioblastoma patients (ref: Cao doi.org/10.1016/j.neo.2025.101156/).

Surgical techniques and imaging advances are critical for improving outcomes in glioblastoma treatment. Molecular-based decision-making in glioblastoma surgery has been enhanced by multi-omics approaches, which provide detailed insights into tumor biology and interactions with the microenvironment, aiding in the determination of when to aim for supramaximal resection (ref: Drexler doi.org/10.1093/neuonc/). A phase 2 study utilizing multiparametric MRI-guided high-dose response-adaptive radiation therapy combined with temozolomide has shown feasibility in targeting hypercellular regions, potentially improving patient outcomes (ref: Kim doi.org/10.1016/j.ijrobp.2025.02.020/). Furthermore, the use of intraoperative 3-T MRI and neuromonitoring has been explored to ensure maximal safe resection while maintaining patient safety and image quality during surgery (ref: Crowe doi.org/10.3171/2024.11.JNS241382/). Advances in gene therapy and natural compounds, such as gracillin, have also shown promise in suppressing cancer progression through the activation of the Hippo signaling pathway (ref: Su doi.org/10.1038/s41401-025-01514-w/). Lastly, unraveling the mechanisms of anoikis in glioblastoma through single-cell sequencing has provided insights into tumor progression and potential therapeutic targets (ref: Tang doi.org/10.1186/s12935-025-03752-8/).

The role of stem cells in glioblastoma recurrence is a critical area of research. One study identified neural stem cells in the subventricular zone as a potential source of tumor reconstruction following primary resection, suggesting that these cells may contribute to glioblastoma recurrence (ref: Li doi.org/10.1186/s12943-025-02273-2/). Another investigation focused on combined targeting of glioblastoma stem cells (GSCs) of different cellular states, revealing specific targets such as MEOX2 and SRGN that mediate resistance to macrophage phagocytosis, highlighting the need for combinatorial targeting strategies (ref: Lu doi.org/10.1038/s41467-025-58366-5/). Furthermore, the polarization of M2 macrophages mediated by Clusterin was identified as a mechanism of temozolomide resistance in GSCs, emphasizing the complex interplay between tumor cells and the immune microenvironment (ref: Wen doi.org/10.1186/s13287-025-04247-z/). The dual-regulation of immunity and metabolism through an acidity-triggered bioorthogonal assembly nanoplatform has also been proposed to enhance glioblastoma immunotherapy, indicating the potential for innovative therapeutic approaches (ref: Wei doi.org/10.1016/j.biomaterials.2025.123216/). Lastly, the dependency on H3K9me3 methyltransferase activity was confirmed through multi-omics analysis, linking it to reduced immune responses and increased tumor proliferation (ref: Xie doi.org/10.1038/s41698-025-00829-5/).

Hypoxia and metabolic adaptations are critical factors influencing glioblastoma progression and treatment response. One study highlighted the dual-regulation of immunity and metabolism via an acidity-triggered bioorthogonal assembly nanoplatform, which enhances glioblastoma immunotherapy by targeting CXCL12/CXCR4 and adenosine-A2AR pathways, indicating the importance of metabolic pathways in tumor immunology (ref: Wei doi.org/10.1016/j.biomaterials.2025.123216/). Additionally, the role of the prostaglandin F2 receptor negative regulator as a potential target for chimeric antigen receptor-T cell therapy in glioblastoma underscores the metabolic adaptations that tumors undergo to evade immune responses (ref: Kuroda doi.org/10.1007/s00262-025-03979-4/). Moreover, a systematic comparison of fetal bovine sera and medium variations on cellular processes revealed significant effects on glioblastoma cell behavior, emphasizing the need for standardized growth conditions in research (ref: Lebedev doi.org/10.3390/cells14050336/). Understanding these metabolic adaptations is crucial for developing effective therapeutic strategies against glioblastoma, particularly in the context of hypoxic tumor microenvironments.

Clinical trials and patient outcomes are pivotal in assessing the efficacy of new treatments for glioblastoma. A multi-institutional phase 1 clinical trial investigated the safety of combining surgical upfront immunotherapy with aglatimagene besadenovec, followed by chemoradiation and adjuvant nivolumab for newly diagnosed glioblastoma patients, aiming to correlate immune activation metrics with clinical outcomes (ref: Wen doi.org/10.1093/neuonc/). Another phase 2 study on multiparametric MRI-guided high-dose response-adaptive radiation therapy combined with temozolomide showed promising results, with interim analysis indicating feasibility and potential improvements in patient outcomes (ref: Kim doi.org/10.1016/j.ijrobp.2025.02.020/). Additionally, a lupus-derived autoantibody that binds to intracellular RNA was found to activate cGAS-mediated tumor immunity, promoting survival in glioblastoma models, highlighting novel therapeutic avenues (ref: Chen doi.org/10.1126/scisignal.adk3320/). Furthermore, the feasibility of hypofractionated intensity-modulated radiation therapy combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) was evaluated, reporting a 6-month progression-free survival rate of 68.3% in newly diagnosed glioblastoma patients (ref: Cao doi.org/10.1016/j.neo.2025.101156/). These studies collectively underscore the importance of innovative treatment strategies and their impact on patient outcomes in glioblastoma management.