Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells have emerged as a promising modern immunotherapeutic strategy, offering advantages over CAR-T cell therapy due to their innate cytotoxicity, safety profile, and potential for scalable, off-the-shelf allogeneic manufacturing. CAR-NK cells can be generated from multiple sources, with recent clinical studies demonstrating notable efficacy and lack of severe toxicity in hematologic malignancies. Nevertheless, the translation of this success to solid tumors is hampered by limited NK cell persistence, trafficking and infiltration challenges, and the hostile, immunosuppressive tumor microenvironment. This review provides a comprehensive synthesis of recent advances and innovations in CAR-NK cell engineering, addresses challenges posed by the solid tumor microenvironment, and highlights both rational preclinical strategies and early-phase clinical trials in solid tumors, underscoring the evolving and transformative promise of CAR-NK therapy for a broader range of human cancers in the near future.

This research examines strategies for reprogramming dendritic cells to counteract tumor-induced immune suppression. Dendritic cells, critical regulators of immune responses, often become dysfunctional within tumor microenvironments, limiting immunotherapy effectiveness. The article explores novel mechanisms through which tumors impair dendritic cell function and presents innovative approaches to restore their antigen-presenting capacity and T-cell activation potential. By understanding and reversing tumor-mediated dysfunction, enhanced dendritic cell reprogramming could significantly improve cancer immunotherapy outcomes, offering promising therapeutic avenues for overcoming immune evasion in oncology.

Glioblastoma remains the most lethal primary central nervous system malignancy with poor prognosis despite conventional treatments. Oncolytic viruses represent an innovative immunotherapy approach that simultaneously destroys tumors and activates antitumor immune responses. However, their clinical efficacy is limited by delivery challenges, including the blood-brain barrier and complex tumor microenvironment. Hydrogels, constructed from natural and synthetic polymers, offer a promising solution by enabling sustained therapeutic payload delivery and facilitating combination treatments with immune checkpoint inhibitors. This review examines advances and obstacles in oncolytic virus therapy, explores hydrogel-mediated delivery mechanisms, and discusses opportunities for synergistic hydrogel-virus-immune adjuvant combinations in treating glioblastoma and other high-grade brain tumors.

The GT-20 trial investigates personalized neoantigen vaccination as a novel immunotherapy approach for glioblastoma, particularly in MGMT-unmethylated patients where conventional treatments have proven ineffective. Led by Elizabeth A. R. Garfinkle and colleagues, this phase 1 study evaluated GNOS-PV01, a customized DNA vaccine targeting up to 40 patient-specific tumor mutations identified through multi-regional sampling and sequencing. By incorporating a broader range of neoantigens than previous platforms, the vaccine aims to enhance immune recognition while minimizing escape mechanisms. The study's primary objective assessed the safety and feasibility of manufacturing and administering such complex personalized vaccines, representing a promising shift toward individualized cancer immunotherapy strategies for this challenging malignancy.

Although FDA-approved drugs are effective, they cause systemic toxicity for their non-specific distribution in healthy organs and tissues, and for this reason, there is urgent need to use biomaterials to develop drug delivery systems to mitigate these side effects. In this context, biomaterials-based delivery systems offer clear advantages by enhancing drug bioavailability, solubility, stability, safety, and controlled release, thereby potentially enhancing therapeutic efficacy while minimizing off-target effects. Despite these advances, the field remains largely preclinical, and a gap persists between promising experimental outcomes and successful clinical implementation. Natural biomaterials, such as hyaluronic acid, alginate, gelatin, and collagen provide intrinsic biocompatibility and bioactivity, yet often suffer from batch variability and limited mechanical tunability. In contrast, synthetic polymers offer greater control over physicochemical properties and scalability but may raise concerns regarding long-term biocompatibility and degradation profiles. Moreover, a limited number of biomaterial-based systems successfully progress to clinical trials, often due to challenges related to their ability to overcome biological barriers such as BBB, stability, large-scale production, administration routes, and in vivo circulation.

This article explores a novel paradigm for glioblastoma immunotherapy centered on meningeal immunity and "interstitial" therapeutic approaches. Glioblastoma, the most aggressive primary brain tumor in adults, presents substantial immunotherapy challenges including the blood-brain barrier, immunosuppressive tumor microenvironment, and limited immune cell infiltration. Recent discoveries of the dural lymphatic system and tissue-resident border-associated macrophages have revealed new opportunities. The proposed "interstitial" immunotherapy strategy shifts focus from the tumor interior to its border regions, leveraging meningeal immune advantages. This review comprehensively examines current GBM immunotherapy limitations, meningeal immunity mechanisms, border-associated macrophage functions, and the theoretical and clinical potential of this innovative approach to enhance therapeutic outcomes and survival.

Between July 2025 and June 2026, numerous clinical trials opened for adult and pediatric patients with primary brain tumors across the United States. This report highlights recently launched studies offering new therapeutic approaches and diagnostic innovations. Notable trials include a phase IIb investigation combining ultrasound sonodynamic therapy with gene therapy for glioblastoma, a phase I/II evaluation of dual-payload gene therapy to enhance anti-tumor immune responses, and a phase I study employing pH-sensitive MRI techniques to identify infiltrating tumor cells and guide surgical resection. Additional trials explore advanced imaging methodologies to assess the tumor immune microenvironment. Patients interested in enrollment are encouraged to consult the provided trial links and contact responsible parties for eligibility criteria and participation details.

Here, Cedars-Sinai Medical Center discusses crossing the blood–brain barrier (BBB), a defining challenge in the development of effective therapies.

Researchers at Washington University School of Medicine have demonstrated promising results from a personalized cancer vaccine trial for glioblastoma, the most aggressive form of brain cancer. The vaccine, called GNOS-PV01, is customized for each patient using engineered DNA that instructs the immune system to recognize and attack tumor-specific proteins called neoantigens. Unlike conventional chemotherapy, which proves ineffective for certain glioblastoma subtypes, this innovative approach leverages the body's own immune defenses. A clinical trial patient with the most aggressive glioblastoma variant has remained cancer-free for nearly five years following vaccination, suggesting the treatment could provide a viable alternative to traditional surgery and radiation for patients with limited options.

Researchers have demonstrated that long-acting interleukin-7 significantly enhances the therapeutic effectiveness of oncolytic viral therapy for treating glioblastoma, an aggressive brain cancer. This immunological approach leverages the cytokine's ability to strengthen immune response mechanisms, enabling viral therapies to more effectively target and eliminate cancer cells. The combination strategy addresses a critical limitation of conventional oncolytic virus treatments by bolstering anti-tumor immunity. These findings suggest promising potential for improving patient outcomes in glioblastoma management, potentially establishing a new therapeutic paradigm that combines immunomodulation with oncolytic viral agents for enhanced clinical efficacy.

CAR-Ms could enhance the efficacy of cancer vaccines. Oncolytic viruses represent another attractive partner, can convert immunologically “cold” tumors

Glioblastoma remains a challenging primary brain malignancy characterized by an immunosuppressive tumor microenvironment, low mutational burden, and molecular heterogeneity. Despite immunotherapy successes in other cancers, glioblastoma treatment efficacy remains limited due to impaired antigen presentation, myeloid-mediated immunosuppression, and blood–brain barrier restrictions. This comprehensive review reconceptualizes the immunotherapeutic landscape through four integrated pillars: enhancing antigen presentation, reversing T cell dysfunction, reprogramming the suppressive microenvironment, and engineering effective intracranial delivery. The synthesis encompasses checkpoint blockade, vaccines, oncolytic virotherapy, and adoptive cellular therapies, highlighting recent clinical advances including bispecific T-cell engagers and emerging CAR T cell designs. By identifying resistance mechanisms and therapeutic convergence points, this framework establishes research priorities to overcome glioblastoma's immunological barriers and enable durable antitumor immunity.

This comprehensive review examines three pivotal approaches in T cell-based cancer immunotherapy: CAR-T therapy, TIL therapy, and T Cell Engagers. Each strategy harnesses cytotoxic T lymphocytes through distinct mechanisms, with CAR-T cells employing synthetic, MHC-independent signaling, TILs leveraging the natural TCR repertoire, and TCEs providing transient pharmacologic bridging. While CAR-T therapy has achieved remarkable success in hematologic malignancies, its application to solid tumors remains limited by hostile tumor microenvironments characterized by immunosuppression and physical barriers. TIL therapy presents a polyclonal alternative suited for solid tumors but encounters manufacturing complexity and variable immunogenicity. TCEs offer convenient off-the-shelf availability yet struggle with persistence and toxicity concerns. The review further explores resistance mechanisms including antigen escape and T cell exhaustion, providing essential insights for advancing immunotherapeutic strategies.

Personalized DNA vaccines represent a significant breakthrough in glioblastoma treatment, offering renewed hope for patients facing this aggressive brain cancer. Researchers have developed a novel immunotherapy approach that harnesses patients' own immune systems by creating custom vaccines from their individual tumor cells. A clinical study published in Nature Cancer demonstrates remarkable outcomes, with nine participants including Kim Garland, who survived nearly five years without recurrence after receiving this targeted treatment. Unlike traditional chemotherapy, this personalized approach trains the immune system to recognize and eliminate cancer cells specifically. Glioblastoma, typically characterized as an immunologically "cold" tumor with mechanisms to evade immune detection, has historically resisted immunotherapy. This innovation addresses those evasion strategies, potentially transforming treatment prospects for this devastating disease that typically claims patients within 12-15 months of diagnosis.

A next-generation CAR T cell immunotherapy targeting the urokinase receptor has eliminated treatment-resistant glioblastoma tumours in preclinical models.

This open-access review examines the complex interaction between oncolytic viruses and tumor microenvironments, exploring how these therapeutic agents overcome the immunosuppressive barriers that protect malignant tumors. The article, published in Cancer Cell International, investigates mechanisms by which oncolytic viruses penetrate tumor defenses and harness immune responses to achieve therapeutic efficacy. By analyzing the dynamic interplay between viral replication, tumor-associated immune suppression, and anti-cancer immunity, the research provides valuable insights for developing enhanced oncolytic viral therapies. The findings contribute to advancing precision oncology strategies and understanding novel approaches to circumvent tumor immune evasion mechanisms, offering promising directions for cancer treatment innovation.

University of California Health is conducting multiple clinical trials for glioblastoma treatment across UCSD and UCSF campuses, open to eligible individuals aged eighteen and older. Studies include the FRONTIER trial evaluating TheraSphere GBM safety in recurrent cases, an investigation of neoadjuvant atezolizumab for recurrent tumors with low mutational burden, and a randomized trial examining ketogenic diet versus standard anti-cancer diet alongside standard treatment in newly diagnosed patients. Additionally, a Phase 3 trial compares niraparib with temozolomide efficacy in newly-diagnosed, MGMT unmethylated glioblastoma, with participants receiving study medication daily during standard radiation therapy. These comprehensive trials aim to advance glioblastoma treatment outcomes through innovative therapeutic approaches and dietary interventions.

UNC Health is leading the way in glioblastoma treatment with a new clinical trial. The study will evaluate the safety and tolerability of CAR-T immunotherapy in patients with recurrent or progressive glioblastoma.

Metabolic rewiring significantly reshapes the tumor microenvironment by altering cellular metabolism to support cancer cell proliferation and metastasis while simultaneously suppressing immune function. Cancer cells preferentially utilize glycolysis over oxidative phosphorylation for energy production, while metabolic changes in lipid metabolism provide essential resources for membrane synthesis and survival. This metabolic reprogramming creates nutrient-depleted, immunosuppressive environments that foster tumor progression and therapeutic resistance. Understanding these intricate metabolic relationships within the tumor microenvironment presents novel therapeutic opportunities, including strategies to modify immune cell metabolism and enhance anti-tumor activity. Combining metabolic inhibitors with conventional therapies may also help overcome resistance mechanisms, offering promising approaches to address cancer as a critical global health burden.

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