Several small natural molecules, such as resveratrol, curcumin, rutin, and icariin, have shown promising anticancer and apoptotic properties in drug-resistant and p53-mutant GBM cell lines. These compounds enhance the antitumor effects of temozolomide (TMZ), targeting glioma stem cells, reducing oxidative stress, preventing cell proliferation, triggering apoptosis, and impeding oncogenic processes. Furthermore, combining these bioactive molecules with advanced drug delivery systems offers potential for improved drug targeting, bioavailability, and blood–brain barrier (BBB) penetration, while minimizing off-target effects.

Macrophages have emerged as promising candidates for cell-based immunotherapies due to their intrinsic plasticity, tissue-infiltrating capabilities, and central roles in orchestrating immune responses. Their phenotypic and functional diversity within tissues and the tumor microenvironment has driven interest in harnessing these cells for therapeutic purposes. Integrating recent knowledge in signaling cascades balancing the activity of macrophages in combination with genetic engineering have enabled the development of macrophages with improved functions, including the introduction of synthetic receptors such as chimeric antigen receptors (CARs). These superior macrophages orchestrate innate immune activity with antigen-specific targeting, offering distinct advantages over conventional CAR-T and CAR-NK cell therapies, especially in solid malignancies. Emerging preclinical and early clinical data support the feasibility, safety, and therapeutic potential of macrophage-based strategies. However, successful clinical translation requires overcoming key challenges in standardization, scalable manufacturing and regulatory compliance of cell products. This review integrates current knowledge in the diversity of macrophage signaling which feeds into engineering techniques, therapeutic applications, and manufacturing innovations. Leveraging concepts of macrophage tissue plasticity highlights the potential of macrophages as next-generation cell therapeutics with broad potential in oncology and beyond, bridging fundamental immunology with translational medicine. Continued interdisciplinary research will accelerate clinical adoption and expand indications across diseases.

Glioblastoma multiforme (GBM) is a highly aggressive and heterogeneous primary brain tumor with poor prognosis and limited therapeutic success. Despite the continued development of surgical and post-surgical treatments, including radiotherapy and chemotherapy, the blood–brain barrier (BBB) hinders treatment efficacy. Intratumoral heterogeneity is the highly invasive behavior of the tumor, causing resistance to treatment. Nanomedicine has emerged as a leading field in addressing the aforementioned challenges through advanced drug delivery methods, highly precise drug targeting to tumors with controlled drug release, and various therapeutic approaches. This review discusses recent developments in nanotherapeutics for GBM. This development focused on the design and use of polymeric, lipid, dendrimeric, inorganic, and hybrid nanocarriers. It discusses multiple methods and approaches that focus on the efficacy of GBM therapeutics through the targeted delivery of nanocarriers (i.e., the use of BBB transport mechanisms, tumor selectivity, receptor-mediated transcytosis, surface functionalization of nanoparticles, and adsorption-mediated transport). It focuses on the use of theranostics to deliver therapeutics, diagnostics, and imaging in a single nanoplatform. This greatly benefits GBM by enabling real-time monitoring of therapeutic delivery and optimizing treatment. It provides a critical overview of the limited clinical applicability of GBM nanotherapeutics. It also highlighted early clinical trials and preclinical evidence as steps toward overcoming therapeutic challenges and providing targeted, advanced therapeutic modalities.

Glioblastoma (GBM) remains a highly aggressive tumor, characterized by its heterogeneity and profound ability to suppress both innate and adaptive immunity. Dendritic cell (DC) vaccines have emerged as a leading immunotherapeutic strategy to counteract this by restoring effective antigen presentation and generating tumor-specific T-cell responses. This review synthesizes two decades of preclinical and clinical research, outlining the biological rationale and translational progress of DC vaccination for GBM. Preclinical studies have been instrumental, demonstrating that the immunogenicity of the antigen cargo, such as whole tumor lysates, neoantigens, and immunogenic cell death products, critically influences DC activation and subsequent T-cell priming. Parallel advances in DC maturation protocols, including p38 inhibition and α-type-1 skewing, have further enhanced vaccine potency. Clinically, DC vaccines have consistently proven safe and capable of inducing systemic and intratumoral immune activation. Late-phase evaluation of DCVax-L has reported an overall survival advantage in newly diagnosed and recurrent GBM using externally controlled comparisons, although interpretation requires caution because of crossover, endpoint changes, patient heterogeneity, and reliance on matched external controls. However, the efficacy of DC monotherapy is often limited by GBM's immunosuppressive microenvironment, suboptimal DC trafficking, and evolving tumor antigenicity.

This article examines stimuli-responsive nanocarriers as advanced delivery systems for therapeutic applications in cancer treatment. Stimuli-responsive nanoparticles, including ultrasound-sensitive liposomes and polymeric nanocarriers, represent a significant innovation in targeted drug and gene delivery. These systems respond to specific triggers such as ultrasound, pH changes, and temperature to release therapeutic payloads on-demand at disease sites. Key applications highlighted include treatment of ovarian cancer stem cells, hepatocellular carcinoma, and glioblastoma, where nanoparticles enhance therapeutic efficacy while minimizing off-target effects. Recent advances demonstrate selective organ targeting using nanoparticles for CRISPR-Cas9 gene editing and blood-brain barrier penetration for glioblastoma therapy. The integration of nanotechnology with gene editing technologies, including CRISPR-based approaches and RNA activation, enables precise genome modification and gene upregulation. These developments hold substantial clinical significance as they overcome limitations of conventional therapies, offering improved precision, reduced toxicity, and enhanced patient outcomes for previously difficult-to-treat cancers and genetic diseases.

This review article, published in Frontiers in Immunology by Wang and colleagues, examines how age and sex function as dual drivers reshaping the anti-tumor immune microenvironment and influencing personalized immunotherapy approaches. The study synthesizes current understanding of immunosenescence—the age-related decline in immune function—alongside sex-based biological differences that affect anti-tumor immunity and immune evasion mechanisms. The authors explore how aging compromises T cell and B cell functionality, reduces natural killer cell activity, and promotes a pro-inflammatory tumor microenvironment that favors cancer progression. Simultaneously, sex hormones and sex chromosome composition create distinct immune profiles between males and females, affecting checkpoint inhibitor responsiveness and immunotherapy outcomes. By integrating these demographic factors into oncology research, the work demonstrates that both age and sex substantially influence tumor immunobiology and treatment efficacy. The findings highlight the critical need for sex-specific and age-stratified approaches in immunotherapy development and clinical trial design, ultimately supporting the shift toward truly personalized immuno-oncology strategies that account for these fundamental biological variables rather than employing one-size-fits-all treatment paradigms.

Researchers have identified a critical regional mechanism underlying diffuse midline glioma development. The study examined how brainstem precursor cells respond to the H3.3 K27M mutation, a hallmark genetic alteration in these aggressive tumors. Unlike precursor cells from other brain regions, brainstem cells exposed to H3.3 K27M demonstrated prolonged immaturity and sustained proliferation, maintaining their dividing state far longer than counterparts elsewhere in the brain. This region-specific cellular response provides important insights into why diffuse midline gliomas preferentially develop in midline structures. The findings suggest that the unique biological properties of brainstem precursor cells—their particular susceptibility to H3.3 K27M-induced changes—may create a permissive environment for tumor initiation and progression. These discoveries have significant implications for understanding gliomagenesis and may inform future therapeutic strategies targeting this devastating pediatric cancer type.

# Summary This comprehensive review examines the immunological mechanisms distinguishing "cold" tumors, which evade immune detection through suppressive microenvironments, from "hot" tumors that attract robust immune responses. The article explores how dysregulation of the cancer-immunity cycle—the sequential process of tumor antigen release, immune cell infiltration, and cytotoxic attack—enables tumor progression. Cold tumors typically exhibit low T-cell infiltration, elevated immunosuppressive signals, and altered antigen presentation, creating an immunologically hostile environment. The review highlights emerging nanotechnology-driven therapeutic approaches designed to convert cold tumors into immunologically active hot tumors. These innovative strategies include nanoparticle-based delivery systems that enhance immunogenicity, facilitate checkpoint inhibitor accumulation, and activate antitumor immunity. The article emphasizes that understanding the immunological determinants underlying tumor phenotypes is crucial for developing effective combination therapies. By integrating nanotechnology with immunotherapy, researchers aim to overcome intrinsic resistance mechanisms and improve treatment outcomes for patients with immunologically "cold" malignancies, representing a significant paradigm shift in personalized cancer treatment strategies.

Immunotherapy represents an emerging therapeutic approach for glioblastoma, one of the most aggressive and difficult-to-treat brain cancers. The article, published in September 2026, explores the application of immunotherapeutic strategies to enhance the body's natural defense mechanisms against glioblastoma cells. Traditional treatment modalities for glioblastoma, including surgery, radiation, and chemotherapy, have limited efficacy and poor prognosis. Immunotherapy offers a promising alternative by leveraging checkpoint inhibitors, CAR-T cell therapies, and cancer vaccines to activate the immune system against tumor cells. The research demonstrates that these approaches can overcome the immunosuppressive microenvironment characteristic of glioblastoma, which typically shields tumors from immune surveillance. Key findings indicate improved survival rates and reduced tumor progression when immunotherapeutic interventions are integrated with conventional treatments. This development is significant for oncology and neuro-oncology fields, as it potentially transforms glioblastoma management from a primarily palliative approach to one offering sustained disease control and improved patient outcomes. The advancement underscores immunotherapy's critical role in next-generation cancer treatment strategies.

CAR T-cell immunotherapy represents a promising approach for treating central nervous system malignancies, including primary brain tumors and brain metastases. This review by Kisamore, Owolabi, Kisamore, and Walker examines the application of chimeric antigen receptor T-cells—engineered immune cells designed to recognize and eliminate cancer cells—in CNS cancer treatment. The article evaluates how adoptive cell transfer technology enables the targeted delivery of CAR T-cells to overcome the blood-brain barrier and address the unique immunological challenges of brain malignancies. By synthesizing current research on CAR T-cell mechanisms, clinical efficacy, and safety profiles specific to CNS applications, the authors highlight both the therapeutic potential and obstacles in this emerging field. This work matters significantly as CAR T-cell therapy offers a novel immunotherapeutic avenue for notoriously difficult-to-treat brain cancers, potentially improving outcomes for patients with limited treatment options and advancing precision cancer immunotherapy strategies.

Optimizing blood-brain barrier penetration remains critical for central nervous system drug development. Physicochemical properties including molecular weight, lipophilicity, hydrogen-bonding capacity, and polar surface area significantly influence passive diffusion across the BBB. However, rational drug design requires balancing multiple parameters rather than maximizing individual ones, as increasing lipophilicity to enhance membrane permeability may simultaneously increase toxicity and nonspecific binding, while reducing polarity can compromise aqueous solubility. Equally important is consideration of efflux transporter susceptibility, particularly P-glycoprotein recognition, which can severely limit brain exposure despite favorable physicochemical properties. Computational modeling, in vitro BBB models, and animal pharmacokinetic studies help identify compounds with improved brain-to-plasma exposure ratios. Receptor-mediated transcytosis represents a promising biological strategy for delivering macromolecules across the BBB by exploiting naturally expressed brain endothelial receptors. The transferrin receptor has attracted substantial attention as a transport vehicle, with antibodies and antibody fragments serving as ligand carriers for therapeutic proteins. Optimization of receptor affinity proves crucial, as excessive binding causes endothelial cell retention, reducing transcytosis efficiency, while insufficient binding fails to facilitate effective transport.

Glioblastoma (GBM) contains a dense collagen-IV-rich extracellular matrix (ECM) that restricts intratumoral transport of therapeutic agents. To overcome this barrier, we engineered protease-responsive, collagenase-functionalized theranostic nanoparticles (TNP-collagenase) by conjugating collagenase-IV to the FDA-approved iron oxide nanoparticle ferumoxytol through a cathepsin B-cleavable linker, enabling tumor-specific enzyme activation. TNP-collagenase retained high MRI relaxivity and exhibited minimal cytotoxicity. In 3D tumor spheroids, TNP-collagenase significantly enhanced nanoparticle penetration compared with ferumoxytol alone. In an orthotopic U87MG mouse model, MRI demonstrated greater tumor accumulation of TNP-collagenase, reflected by significantly reduced tumor T2 relaxation times. TNP-collagenase combined with temozolomide (TMZ) induced significant tumor regression compared with PBS + TMZ and ferumoxytol + TMZ. Histological analyses confirmed degradation of perivascular collagen-IV and improved intratumoral distribution of therapeutics. These results establish enzyme-activated ECM remodeling as a nanomedicine strategy to enhance drug delivery and therapeutic efficacy in GBM while enabling noninvasive imaging of treatment response.

Therapeutic cancer vaccines have historically faced limited clinical efficacy, with Sipuleucel-T being the only FDA-approved option until recently. However, personalized mRNA vaccines—notably Moderna's mRNA-4157 and BioNTech's autogene cevumeran—have demonstrated substantial improvements in recurrence reduction and survival outcomes, revitalizing the field. These vaccines leverage patient-specific tumor antigens to generate targeted immune responses. The review examines multiple vaccine platforms including DNA-, mRNA-, peptide-, dendritic cell-, and whole-cell-based approaches, while addressing challenges such as tumor heterogeneity and immunosuppressive microenvironments. Advanced delivery systems utilizing lipid-polymer hybrids, biomimetic membranes, and stimulus-responsive nanovaccines enhance lymph node targeting and dendritic cell activation. Integration with artificial intelligence for antigen selection and multiomics for patient stratification optimizes vaccine design precision. Combination therapies with immune checkpoint inhibitors further enhance efficacy. Clinical evidence, particularly in melanoma and pancreatic cancer, demonstrates these strategies' potential for durable antitumor immunity and long-term protection, marking a significant shift toward precision cancer immunotherapy.

Renal cell carcinoma remains a significant clinical challenge despite the success of immune checkpoint inhibitors, as primary and acquired resistance, patient heterogeneity, and systemic toxicity continue to limit treatment effectiveness. The disease employs three interconnected immune evasion mechanisms: defective immune priming combined with checkpoint-mediated immunosuppression, vascular-metabolic barriers that prevent immune cell infiltration and function, and a suppressive tumor microenvironment orchestrated by myeloid cells, regulatory lymphocytes, cytokines, and extracellular vesicles. These multilayered barriers collectively impair effector cell function and drive T-cell exhaustion. This comprehensive review published in the International Journal of Nanomedicine examines how nanodelivery platforms can overcome these immunosuppressive constraints through programmable payload delivery, spatiotemporally controlled local release, and material-mediated tumor microenvironment modulation. The authors systematically discuss intervention strategies targeting antigen presentation restoration, innate immune sensing activation, effector cell maintenance, vascular-metabolic remodeling, and suppressive immune network reprogramming. The review compares lipid-based, polymeric, and inorganic nanoplatforms, providing crucial insights for developing next-generation combination therapies to enhance RCC treatment outcomes.

Researchers have developed an innovative engineered macrophage therapy called signal-switching receptor CAR-macrophages (SR CAR-Ms) to overcome the immunosuppressive barriers that limit conventional CAR-T cell therapy in solid tumors. These macrophages are engineered to recognize interleukin-10 (IL-10), a major immunosuppressive cytokine abundant in solid tumors, and convert this inhibitory signal into pro-inflammatory activation through Toll-like receptor 9 (TLR9) signaling. In preclinical studies using an orthotopic 4T1 breast cancer model, SR CAR-Ms selectively accumulated in tumors, depleted local IL-10, induced inflammatory cytokine production, suppressed tumor growth, and prolonged survival without systemic toxicity. The engineered macrophages adopted an M1-like phenotype with enhanced phagocytic capacity and promoted dendritic cell maturation while preventing T cell exhaustion. Further advancement was achieved by creating dual-function SRPα CAR-Ms that also secreted anti-PD-L1 antibodies, outperforming monotherapies alone. This signal-switching paradigm transforms an immunosuppressive cytokine into a location-specific activation trigger, offering a promising new strategy for treating solid malignancies resistant to conventional immunotherapies.

Cancer stem cells (CSCs) drive tumor metastasis, recurrence, and drug resistance by maintaining stemness through redox homeostasis, metabolic plasticity, and specialized microenvironmental niches. This comprehensive review examines stimuli-responsive nanomaterials designed to modulate CSCs for improved therapeutic outcomes. Rather than employing conventional cytotoxic approaches that eliminate non-CSCs while allowing CSCs to survive and regenerate tumors, the field is shifting toward fate regulation strategies that reprogram cellular behavior and disrupt stemness-related networks. The review details the rational design of smart nanoplatforms responsive to both endogenous tumor microenvironment triggers and exogenous physical fields, explaining how these synergized platforms precisely modulate cellular behaviors. Key translational challenges are identified, including the need for real-time CSC monitoring and development of biomimetic organoid models to intercept intercellular communications. The work provides a structural roadmap for developing next-generation multimodal nanotechnologies to achieve efficient CSC modulation and anti-tumor treatment, representing a significant paradigm shift from simple elimination to sophisticated cellular reprogramming strategies.

Natural killer cells possess inherent capacity to eliminate transformed cells without prior sensitization, yet their therapeutic effectiveness against solid tumors remains limited. This paradox stems from complex inhibitory pathways centered on killer cell immunoglobulin-like receptors and the CD94/NKG2A axis, which regulate NK-cell tolerance and function. Tumors evade immune surveillance by dynamically remodeling HLA-I expression, preserving non-classical HLA-E to sustain inhibitory signaling. The tumor microenvironment further suppresses NK-cell activity through stromal barriers, hypoxia, metabolic stress, and immunosuppressive networks that impair infiltration and cytotoxicity. Consequently, therapeutic blockade of KIR or NKG2A alone has produced only modest clinical benefits in solid tumors despite strong biological rationale. This analysis, conducted by researchers at Italian institutions including the University of Genoa and University of Udine, positions the KIR and CD94/NKG2A network as both therapeutic target and framework for next-generation NK-cell immunotherapies. Future approaches will likely integrate checkpoint modulation with donor- and patient-tailored NK-cell selection, engineered NK-cell products with enhanced metabolic resilience, and tumor microenvironment remodeling strategies to overcome multilayered immune suppression.

CAR-T cell therapy has achieved remarkable success in hematological malignancies, but its activity in solid tumors remains constrained by multiple interrelated barriers. The scarcity of truly tumor-specific antigens, together with heterogeneous or low-density target expression and antigen loss, can impair tumor recognition and promote immune escape. Even when target antigens are present, CAR-T cells often fail to reach and penetrate tumor lesions because of chemokine–receptor mismatch, abnormal tumor vasculature, and extracellular matrix-rich stromal barriers. Within the tumor bed, checkpoint signaling, suppressive cytokines and immune cells, and metabolic stress further limit CAR-T cell expansion, persistence, and cytotoxic function. These linked obstacles suggest that improving therapeutic outcomes in solid tumors requires more than enhancing CAR-T-cell killing capacity alone.

The effectiveness of cancer immunotherapy may depend not only on which immune cells reach a tumor, but also on when they arrive. Researchers from Sungkyunkwan University and Seoul National University College of Medicine have demonstrated that the sequence of interactions between immune cells and glioblastoma cells can significantly influence treatment response. Their findings, published in Neuro-Oncology, suggest that timing is an overlooked factor in the tumor microenvironment and could become an important consideration in the development of personalized immunotherapies for one of the deadliest forms of brain cancer.

Nucleic acid-based therapeutic molecules including small interfering RNA (siRNA), microRNA(miRNA), antisense oligonucleotides (ASOs), messenger RNA (mRNA), and DNA-based gene therapy have tremendous potential for treating diseases in the central nervous system (CNS). However, achieving clinically meaningful delivery to the brain and particularly to target cells and sub-cellular compartments is typically very challenging. Mediating cell-specific delivery in the CNS would be a crucial advance that mitigates off-target effects and toxicities. In this review, we describe these challenges and provide contemporary evidence of advances in cellular and sub-cellular delivery using a variety of delivery mechanisms and alternative routes of administration, including the nose-to-brain approach. Strategies to achieve subcellular localization, endosomal escape, cytosolic bioavailability, and nuclear transfer are also discussed. Ultimately, there are still many challenges to translating these experimental strategies into effective and clinically viable approaches for treating patients.