Aug 2026· Nature Reviews Clinical Oncology· 0 citations· 198 references
Medicine
TL;DR
The therapeutic landscape of targeted therapies in glioblastomas is summarized, spanning major target classes including receptor tyrosine kinases, intracellular signalling proteins, cell-cycle dysregulation and synthetic-lethal vulnerabilities and emerging strategies targeting genome integrity and telomeres, epigenetic modulators, and tumour-neural circuitry are examined.
Abstract Background: Glioblastoma multiforme (GBM) is the most aggressive primary malignant brain tumor in adults and remains associated with poor survival despite advances in surgery, radiotherapy, and chemotherapy. Increasing evidence suggests that IDH-wildtype glioblastoma progression is driven by complex interactions between dysregulated molecular signaling pathways, intratumoral heterogeneity, glioma stem cells, and immune suppression within the tumor microenvironment. Objective: This narrative review summarizes the major signaling pathways implicated in GBM pathogenesis, including EGFR, PI3K/AKT/mTOR, Wnt, and TGF-β signaling, while also discussing emerging therapeutic targets such as FGFR3–TACC3 fusions, regorafenib, and natural killer cell-based immunotherapy. Results The review further examines mechanisms underlying treatment resistance and the limitations of current targeted therapies. Although many pathway-directed treatments have demonstrated promising preclinical activity, clinical translation remains challenging because of compensatory signaling, blood–brain barrier limitations, and molecular heterogeneity. Conclusion: Future progress will likely depend on biomarker-driven patient stratification, improved CNS drug delivery, and rational combination therapies capable of simultaneously targeting multiple tumor-promoting mechanisms.
William W Li, Jia Ming Chen, Yiying Ma· Future Science OA· 0 citations
Glioblastoma (GBM) remains one of the most aggressive primary brain tumors, with poor prognosis, high recurrence, and limited therapeutic options. Although substantial progress has been made in drug development, effective clinical translation is still constrained by inefficient delivery across the blood brain barrier (BBB) and blood brain tumor barrier (BBTB), insufficient tumor accumulation, intratumoral heterogeneity, acquired therapeutic resistance, and dose limiting systemic toxicity. Nanomedicine offers a promising strategy to address these barriers through tunable physicochemical properties, flexible surface functionalization, improved pharmacokinetics, and controllable drug release. In this review, we systematically summarize recent advances in nanomedicine enabled GBM therapy from four interrelated perspectives: the optimization of nanomaterial properties, the development of goal-oriented targeting strategies, the rationalization of delivery routes, and the engineering of smart stimuli-responsive nano-systems. Rather than only cataloguing representative nanoplatforms, we emphasize how material parameters, biological targeting mechanisms, delivery routes, and release behaviors are mechanistically linked to BBB or BBTB penetration, tumor accumulation, therapeutic efficacy, and translational feasibility. Importantly, we also incorporate a key failure case analysis of representative clinical and preclinical studies, highlighting why promising nanotherapeutic concepts may fail because of inadequate intratumoral distribution, insufficient survival benefit, poor patient selection, manufacturing complexity, safety concerns, or impractical trial design. By integrating delivery mechanisms, cross platform comparison, translational barriers, and future optimization principles, this review provides a critical and forward looking framework for the rational design of precise, effective, and clinically translatable nanomedicine strategies for GBM treatment.
Yu Guo, Keqiang Lu, Wenmiao Luo et al.· Wiley Interdisciplinary Revi...· 1 citation
Glioblastoma (GBM) is an intricate intracranial tumor that has cataclysmic outlook. It originates from glial cells having an average life expectancy of one and a half years. Despite intensive multimodal therapy, the tumor's innate invasiveness and cellular heterogeneity lead to nearly inevitable recurrence. Recent advancements have shifted the focus toward the interplay between genetic drivers and the dynamic epigenetic landscape. WHO classification defined GBM as an IDH-wildtype tumor, distinguishing it from IDH-mutant. Present review explores the complex epigenetic mechanisms such as DNA methylation, histone modification and RNA editing that drive GBM progression, shape the tumor microenvironment and facilitate immune evasion. The review further discusses severe translational barriers, including blood brain barrier penetrance, tumor heterogeneity, and the immunosuppressive effects of steroids. Finally, we highlight the therapeutic potential of targeting these epigenetic vulnerabilities through inhibitors of histone deacetylase and DNA methyltransferase, either alone or combined with modern immunotherapies to overcome treatment resistance and improve patient outcomes.
High‐grade central nervous system cancers incur a significant burden of care on society. The combination of therapeutic resistance and high mortality makes it both a challenging target and a devastating diagnosis. Of these, one in two is characterized as glioblastoma (GBM) with a median survival rate of only 13.5 months with the current standard of therapy. Modern interventions, such as PD‐1 and CTLA‐4 checkpoint inhibition and autologous CAR T cell delivery, remain stymied by both the difficult nature of drug delivery to the brain and the inherent immunosuppressive tumor microenvironment. However, recent advances in the characterization of GBM have unveiled promising new therapeutic avenues aiming to target and eliminate the tumor. In this review, we summarize the mechanisms through which GBM is initiated, localized, and eludes therapy responses and provide an update on recent advances made within this therapeutic space to overcome GBM‐mediated immunosuppression. We also discuss the challenges with current and next generational treatment strategies before finally exploring the landscape of potential future therapeutic targets.
Emerson Achari, Farah Ahmady-Nield, Amit Sharma et al.· Immunology and Cell Biology· 0 citations
Brain-metastatic breast cancer (BMBC) is a severe complication of advanced breast cancer, affecting 15-30% of metastatic patients, particularly those with HER2-positive or triple-negative subtypes, and is associated with dismal prognosis and median survival under 12 months. Therapeutic resistance, driven by the central nervous system's sanctuary role, poses a major barrier to effective treatment, often resulting in discordant intracranial versus extracranial responses. This comprehensive review highlights BMBC resistance mechanisms, drawing from preclinical models, clinical studies, and genomic analyses. Key drivers include genetic/epigenetic alterations, BBB-mediated drug exclusion via efflux transporters, and microenvironmental interactions with astrocytes and immune cells that promote survival signaling. Additional factors encompass cancer stem cell plasticity/dormancy enabling therapy evasion, metabolic reprogramming and extracellular matrix remodeling that shields tumor from drugs. We highlight how these interconnected pathways create a protective niche for metastatic cells. Promising strategies to overcome resistance include BBB-penetrant agents, antibody-drug conjugates, nanomedicine, and combination therapies targeting the tumor microenvironment and epigenetics. By integrating mechanistic insights with translational opportunities, this review emphasizes the potential for personalized, multi-targeted approaches to improve patient outcomes in BMBC.
Paromita Sarker, Shreyas S Rao· Biochimica et biophysica act...· 0 citations
Glioblastoma (GBM) remains one of the most lethal brain malignancies, characterized by aggressive invasion, therapeutic resistance and poor prognosis. Conventional treatment approaches are limited by systemic toxicity, poor blood–brain barrier (BBB) penetration and lack of tumor specificity. Nanoparticle-based therapeutics offer a transformative paradigm redefining drug delivery, diagnostics and multimodal strategies in GBM. In this review, we critically explore a diverse variety of advanced nanocarrier platforms designed for anti-proliferative, radiosensitizing and immunomodulatory interventions. These systems enhance BBB penetration, tumor localization and enable co-delivery of chemotherapeutics, gene therapies and imaging agents with high precision. Innovative approaches show efficacy against glioma stem cells, modulate the tumor microenvironment and address resistance mechanisms. Integration with radiotherapy and immunotherapy yields synergistic tumor suppression and immune activation, advancing personalized nanomedicine. Despite these advancements, translational hurdles remain nanogenotoxicity, long-term biosafety, immune responses and regulatory barriers. This review emphasizes such challenges while identifying opportunities for strategic innovation in GBM nanotherapy. By uniquely bridging preclinical advances with emerging clinical perspectives, we highlight its distinct contribution within the field. By bridging nanotechnology, molecular oncology and bioengineering, we highlight how rational nanoparticle design can shift GBM management toward targeted, multimodal precision therapy, offering renewed hope against one of oncology’s most intractable diseases.
Keywords: Glioblastoma, Nanoparticles, Blood-Brain Barrier, Nanotechnology, Nanomedicine, Nanotherapeutics.