Despite transforming oncology, immune checkpoint inhibitors, adoptive cell therapies, and cancer vaccines remain limited by immune exclusion—the failure of effector immune cells to penetrate or function effectively within the tumor microenvironment (TME). This exclusion stems from dense extracellular matrices, immunosuppressive cells including regulatory T cells and tumor-associated macrophages, and inhibitory signaling molecules such as PD-L1, TGF-β, and adenosine. A new Research Topic aims to integrate fundamental, translational, and clinical research to overcome these barriers and reprogram the TME. The initiative encourages studies exploring novel approaches including targeted protein degradation via PROTACs and molecular glues, ubiquitination modulation, and deubiquitinase inhibitors, alongside combination strategies with checkpoint inhibitors, CAR-T, and NK-cell therapies. Additional focus areas include chemotherapy and radiotherapy combinations, biomarker discovery, and clinical translation of TME-targeted interventions. By fostering cross-disciplinary collaboration, this Research Topic seeks to accelerate bench-to-bedside translation of TME-modulating immunotherapies, potentially expanding immunotherapy benefits to broader patient populations across diverse tumor types.

Glioblastoma, the most aggressive form of brain cancer, remains exceptionally difficult to treat despite standard interventions including surgery, radiotherapy, and temozolomide chemotherapy, with recurrence presenting a major clinical challenge. A recently published real-world study examined 173 glioblastoma patients treated with personalized neoantigen-derived peptide vaccines, representing a significant advance in individualized cancer immunotherapy. The personalized peptides analyzed in this research were synthesized by Intavis Peptide Services GmbH in Tuebingen, Germany. This innovation exemplifies the shift toward tumor-specific treatment strategies that account for the molecular heterogeneity inherent in glioblastoma. Accompanying the scientific publication, a patient testimonial from CeCaVa provides compelling evidence of the potential impact, with one patient, Rebecca, describing extended survival beyond her initial devastating prognosis. While her case cannot be generalized to all patients, it underscores the critical importance of developing and providing access to personalized therapeutic approaches that leverage each tumor's unique molecular profile, offering hope for improved outcomes in this otherwise incurable disease.

Neoantigen-based cancer immunotherapies, including vaccines, adoptive cell therapies, and immune checkpoint inhibitors, represent a transformative approach to personalized cancer treatment by targeting tumor-specific mutations while sparing healthy tissues. Current identification methods such as next-generation sequencing and immunopeptidomics have advanced neoantigen discovery, yet significant challenges remain. Epitope prediction accuracy remains suboptimal, requiring refined computational workflows, while experimental validation is resource-intensive and time-consuming. Emerging technologies like T-Scan offer potential for scaling T cell assessment processes, but more efficient TCR mapping, high-throughput platforms, and enhanced algorithms are essential. Financial and temporal constraints pose additional barriers to widespread implementation of personalized therapies. Developing off-the-shelf treatments targeting public neoantigens—common mutations across tumor types—presents a promising solution to reduce costs and timelines, though effectively targeting shared neoantigens remains scientifically challenging. Future research should prioritize developing public neoantigen-based vaccines, bispecific antibodies, and TCR-based therapies. Combination approaches, particularly pairing neoantigen vaccines with immune checkpoint inhibitors alongside chemotherapy or radiation, demonstrate enhanced efficacy and represent the most promising path forward for advancing precision cancer immunotherapy.

# Summary Researchers at the University of Florida have reported encouraging preliminary results from the first human trial of an RNA-based vaccine designed to treat glioblastoma, an aggressive form of brain cancer. The personalized medicine approach, developed through the iOncologi platform, represents a novel application of RNA technology to immuno-oncology. Rather than preventing disease, this vaccine is administered therapeutically to stimulate the immune system to recognize and attack cancer cells specific to individual patients. The trial demonstrates the feasibility of tailoring RNA vaccines to target tumor-specific mutations, offering a promising avenue for improving glioblastoma treatment outcomes. These findings are significant as glioblastoma remains one of the most challenging cancers to treat, with limited therapeutic options. The success of this approach could potentially extend RNA vaccine applications beyond infectious diseases into personalized cancer therapy, potentially transforming treatment paradigms for difficult-to-treat malignancies and opening pathways for similar immunotherapy strategies across other cancer types.

CAR T-cell therapy shows promise for hematologic malignancies but faces significant challenges in solid tumors, particularly glioblastoma, due to tumor heterogeneity, immunosuppression, and antigen loss. A 2026 Cell study analyzed 18 patients from a phase 1 trial receiving intracerebroventricular EGFR/IL13Rα2-targeted CAR T cells, employing single-cell RNA sequencing to profile cerebrospinal fluid, infusion products, and tumor tissues. The research revealed that clinical outcomes depended not only on CAR T-cell activity but also on host immune remodeling. CD8 CAR T cells demonstrated robust activation with upregulation of cytotoxicity genes including GZMB, GNLY, and PRF1, peaking around day 7 before showing exhaustion markers by day 21. Critically, expansion of endogenous cytotoxic NK cells correlated with favorable outcomes, while regulatory T-cell and suppressive myeloid expansion associated with poorer responses. Notably, CAR T infusion product characteristics alone did not distinguish responders from non-responders. These findings underscore that treatment success involves complex host immune remodeling beyond the engineered T cells themselves, offering important insights for optimizing CAR T-cell therapy in challenging solid tumor settings.

Researchers have identified a critical mechanism by which endocrine-resistant hormone receptor-positive (HR+) breast cancer cells evade immune surveillance through lipid metabolic reprogramming. The study, published in Frontiers in Immunology, reveals that cancer cells undergoing endocrine resistance simultaneously reprogram their lipid metabolism to suppress anti-tumor immune responses. This metabolic shift causes defects in antigen presentation, the process by which cancer cells display tumor antigens to immune cells, and induces T-cell dysfunction, impairing the ability of immune cells to recognize and eliminate cancer cells. By understanding this dual mechanism of therapeutic resistance and immune evasion, the findings offer important insights into why HR+ breast cancers often develop resistance to hormonal therapies. This discovery has significant implications for developing combination therapeutic strategies that target both endocrine resistance and lipid-driven immune evasion, potentially improving outcomes for patients with advanced HR+ breast cancer who no longer respond to standard hormone-based treatments.

Researchers have developed an innovative photothermal immunotherapy strategy to enhance cancer treatment by precisely controlling tumor temperature during hyperthermia treatment. The study addresses a critical gap in understanding the thermal parameters needed for optimal immune activation in tumor microenvironments. The team created ACF@QD, a photothermal immuno-nanomedicine combining multiple functional components: AF7P for tumor cell targeting, FS-mPEG as a photothermal agent, AgAuSe quantum dots for real-time temperature monitoring via near-infrared-II imaging, and CpG oligonucleotides to enhance macrophage and dendritic cell function. Using spatiotemporally encoded laser irradiation guided by NIR-II fluorescence feedback, researchers achieved precise in vivo temperature regulation and demonstrated that 46°C represents the optimal temperature threshold for synergistically activating immunogenic cell death and immune cell recruitment in breast cancer models. This breakthrough establishes evidence-based thermal parameters for hyperthermia-based immunotherapy and provides a versatile platform for investigating temperature-dependent immune mechanisms in cancer treatment.

This comprehensive review examines nanomedicine strategies designed to remodel the hostile tumor microenvironment and improve therapeutic efficacy. Rather than targeting malignant cells alone, the authors address stromal fibroblasts, extracellular matrix components, abnormal vasculature, hypoxia, and immunosuppressive populations that collectively impede drug delivery and treatment response. The analysis focuses on three interconnected approaches: stromal remodeling using cancer-associated fibroblast-directed and matrix-responsive carriers to enhance perfusion, hypoxia control through oxygen-generating and hypoxia-activated systems alongside Type I photochemical strategies, and photodynamic immune activation via immune-active nanocarriers including STING agonists and mRNA vaccines. The authors emphasize that selective fibroblast reprogramming is preferable to depletion, which can worsen outcomes, and highlight pancreatic ductal adenocarcinoma as a key desmoplastic disease model while comparing it with glioblastoma and other tumors with distinct microenvironments. The review identifies translational barriers including variable tumor delivery, protein corona formation, and manufacturing complexity, advocating for biomarker-guided, mechanism-matched platforms with measurable microenvironmental endpoints rather than increasingly complex carrier designs as the realistic path forward.

Immunotherapy resistance in solid tumors extends beyond molecular and cellular immune suppression to include profound mechanical abnormalities within the tumor microenvironment (TME). This review examines how mechanical features—including extracellular matrix stiffening, altered cellular stiffness, elevated solid stress, abnormal fluid shear stress, and increased interstitial fluid pressure—regulate antitumor immunity and promote immunotherapy resistance. The authors analyze how these mechanical properties influence the cancer-immunity cycle, from tumor-antigen release through immune-cell infiltration to cytotoxic killing. The paper identifies tumor mechanical properties as functional immune checkpoints facilitating immune evasion. Emerging therapeutic strategies targeting extracellular matrix remodeling, cancer-associated fibroblasts, vascular dysfunction, interstitial fluid pressure, and mechanotransduction pathways show promise in improving immunotherapy efficacy, though evidence is predominantly preclinical. Integrating mechanical properties into cancer immunology provides a comprehensive framework for understanding immunotherapy resistance in solid tumors and developing rational combination treatment strategies.

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.