Glioblastoma (GBM) remains the most aggressive and lethal brain tumor in adults and poses significant challenges to patient survival. This review provides a comprehensive exploration of the molecular and genetic landscape of GBM, focusing on key oncogenic drivers, such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), and the PI3K/AKT/mTOR pathway, which are critical for tumorigenesis and progression. We delve into the role of epigenetic alterations, including DNA methylation and histone modifications, in driving therapy resistance and tumor evolution. The tumor microenvironment is known for its pivotal role in immune evasion, with tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells creating an immunosuppressive niche that sustains GBM growth. Emerging therapies, such as immunotherapies, oncolytic viral therapies, extracellular vesicle-based approaches, and non-coding RNA interventions, are highlighted as promising avenues to disrupt GBM pathogenesis. Advances in precision medicine and innovative technologies, including electric field therapy and locoregional treatments, are discussed for their potential to overcome the blood‒brain barrier and treatment resistance. Additionally, this review underscores the importance of metabolic reprogramming, particularly hypoxia-driven adaptations and altered lipid metabolism, in fueling GBM progression and influencing the therapeutic response. The role of glioma stem cells in tumor recurrence and resistance is also emphasized, highlighting the need for targeted therapeutic approaches. By integrating molecular targeting, immune energetics, and technological advancements, this review outlines a multidisciplinary framework for improving GBM treatment outcomes. Ultimately, the convergence of genetic, metabolic, and immune-based strategies offers transformative potential in GBM management, paving the way for increased patient survival and quality of life.

Glioblastoma remains the most aggressive and treatment-resistant brain malignancy, driven by genetic heterogeneity, metabolic plasticity, and an immunosuppressive tumor microenvironment (TME). Current therapies rely on inducing tumor cell death through DNA damage; however, glioma stem cells (GSCs) upregulate compensatory DNA repair pathways, promoting resistance and tumor recurrence. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, offers a novel therapeutic strategy to overcome therapy resistance by exploiting glioblastoma’s metabolic vulnerabilities. Unlike conventional therapies, ferroptosis bypasses DNA repair mechanisms, making it particularly effective against therapy-resistant GSCs. It reduces tumor growth by triggering iron-catalyzed oxidative stress, disrupting lipid metabolism, and pushing glioblastoma cells beyond their oxidative threshold. However, resistance mechanisms to ferroptosis, including iron metabolism regulators (IREB2 and ferritinophagy), lipid peroxidation enzymes (ACSL4 and ALOXs), and protective pathways (cystine transporters and glutathione peroxidase 4), limit its therapeutic potential. Extracellular vesicle-mediated iron transfer further contributes to ferroptosis resistance, fostering chemoresistance and radio-resistance. Beyond direct tumor killing, ferroptosis modulates the TME by releasing damage-associated molecular patterns, inducing reactive oxygen species, stimulating CD8⁺ T-cell activation, enhancing immune checkpoint blockade efficacy, and reprogramming tumor-associated macrophages toward an anti-tumor phenotype. Ferroptosis-based strategies, including glutathione peroxidase 4 inhibitors, nanoparticle-mediated iron delivery, and RNA-based therapies, offer promising avenues for enhancing glioblastoma treatment efficacy. This review highlights ferroptosis as a promising strategy for overcoming glioblastoma resistance by integrating it with chemotherapy, radiotherapy, and immunotherapy to enhance treatment efficacy. Given the complexity of glioblastoma, personalized ferroptosis-based approaches that address tumor heterogeneity, immune interactions, and metabolic adaptations are crucial for overcoming therapy resistance. Refining ferroptosis-targeted strategies by incorporating metabolic, immune, and genetic considerations can lead to more durable and effective therapies, ultimately transforming glioblastoma treatment and improving patient outcomes.

Significance: The proliferation of viral pathogens is restricted by hosts, but resilient pathogens antagonize the restriction by hosts. Findings explain that HIV-1 blocked mono-methylated guanosine cap by hypermethylation and engaged novel cap-binding complex for virion protein translation unaffected by global translation inhibition. The hypermethylated cap activity required RNA-structure-dependent binding of RNA helicase A/DHX9. eIF4E interaction proceeded on completely spliced HIV messenger RNA templates encoding viral regulatory proteins, thus eIF4E inactivation by catalytic site mTOR inhibitor suppressed regulatory protein translation, while structural/accessory protein translation was maintained. Two mutually exclusive translation pathways antagonize hosts and facilitate HIV-1 proliferation in primary CD4 ⁺ T cells to the detriment of hosts. eIF4E inactivation imposed an operational rheostat that suppressed regulatory proteins, while maintaining virion production in immune cells.

Conventional and cancer immunotherapies encompass diverse strategies to address various cancer types and stages. However, combining these approaches often encounters limitations such as non-specific targeting, resistance development, and high toxicity, leading to suboptimal outcomes in many cancers. The tumor microenvironment (TME) is orchestrated by intricate interactions between immune and non-immune cells dictating tumor progression. An innovative avenue in cancer therapy involves leveraging small molecules to influence a spectrum of resistant cell populations within the TME. Recent discoveries have unveiled a phenotypically diverse cohort of innate-like T (ILT) cells and tumor hybrid cells (HCs) exhibiting novel characteristics, including augmented proliferation, migration, resistance to exhaustion, evasion of immunosurveillance, reduced apoptosis, drug resistance, and heightened metastasis frequency. Leveraging small-molecule immunomodulators to target these immune players presents an exciting frontier in developing novel tumor immunotherapies. Moreover, combining small molecule modulators with immunotherapy can synergistically enhance the inhibitory impact on tumor progression by empowering the immune system to meticulously fine-tune responses within the TME, bolstering its capacity to recognize and eliminate cancer cells. This review outlines strategies involving small molecules that modify immune cells within the TME, potentially revolutionizing therapeutic interventions and enhancing the anti-tumor response.

The mTOR signaling pathway plays a pivotal and intricate role in the pathogenesis of glioblastoma, driving tumorigenesis and proliferation. Mutations or deletions in the PTEN gene constitutively activate the mTOR pathway by expressing growth factors EGF and PDGF, which activate their respective receptor pathways (e.g., EGFR and PDGFR). The convergence of signaling pathways, such as the PI3K-AKT pathway, intensifies the effect of mTOR activity. The inhibition of mTOR has the potential to disrupt diverse oncogenic processes and improve patient outcomes. However, the complexity of the mTOR signaling, off-target effects, cytotoxicity, suboptimal pharmacokinetics, and drug resistance of the mTOR inhibitors pose ongoing challenges in effectively targeting glioblastoma. Identifying innovative treatment strategies to address these challenges is vital for advancing the field of glioblastoma therapeutics. This review discusses the potential targets of mTOR signaling and the strategies of target-specific mTOR inhibitor development, optimized drug delivery system, and the implementation of personalized treatment approaches to mitigate the complications of mTOR inhibitors. The exploration of precise mTOR-targeted therapies ultimately offers elevated therapeutic outcomes and the development of more effective strategies to combat the deadliest form of adult brain cancer and transform the landscape of glioblastoma therapy.