CAR-T cell therapy has transformed the treatment of several haematological malignancies, but its impact in solid tumours has remained frustratingly limited. Now, a new generation of in vivo CAR-T cell technologies promises to remove some of the biggest practical barriers associated with conventional cell therapy.

The tumor mechanical microenvironment (TMME) significantly influences cancer initiation, progression, metastasis, and treatment response through physical cues including matrix stiffness, solid stress, interstitial fluid flow, and extracellular matrix architecture. Traditional in vitro and in vivo models inadequately capture the dynamic, heterogeneous mechanical characteristics of native tumors. This comprehensive review examines advances in modeling the TMME using tumor organoids, particularly patient-derived tumor organoids (PDOs), which maintain tumor architecture, cellular heterogeneity, and genetic background while enabling precise experimental control and high-throughput analysis. The authors discuss major mechanical features of the tumor microenvironment and strategies for recreating these features in organoid models, including stiffness-defined matrices, engineered extracellular matrices, microfluidic platforms, mechanical actuation systems, multicellular co-culture approaches, and three-dimensional bioprinting techniques. The review emphasizes applications in mechanistic studies, disease modeling, and drug testing, highlighting how organoid-based platforms represent physiologically relevant alternatives for understanding tumor mechanics and improving therapeutic strategies.

Triple-negative breast cancer (TNBC), representing 15-20% of breast cancer cases, lacks expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), rendering conventional targeted therapies ineffective and resulting in poorer clinical outcomes. A critical challenge in TNBC treatment is chemoresistance development through mechanisms including drug efflux transporter upregulation, altered apoptotic pathways, enhanced DNA repair, and epithelial-mesenchymal transition, compounded by tumor microenvironment factors such as hypoxia and acidic pH. Conventional chemotherapy's non-specific drug distribution causes systemic toxicity while failing to accumulate in chemoresistant tumor niches. To overcome these limitations, researchers are advancing stimuli-responsive nanocarriers that enable selective, controlled drug delivery triggered by tumor-specific stimuli including pH, enzymes, temperature, and redox conditions. These nanofabricated carriers enhance drug bioavailability, facilitate intracellular delivery, overcome efflux mechanisms, and modulate the tumor microenvironment. Nanofabrication techniques enable precise control over nanocarrier size, shape, surface characteristics, and drug release profiles, optimizing therapeutic outcomes and addressing key mechanisms underlying TNBC chemoresistance.

Recent research demonstrates significant advancement in natural killer (NK) cell-based immunotherapies across multiple cancer types. A phase II trial combined sequential hypofractionated radiotherapy with atezolizumab for relapsed small cell lung cancer, using objective response rate as the primary measure. NK cell therapies have shown particular promise in hepatocellular carcinoma, where radiation-induced tumor-cell phenotypic changes were evaluated to support primary NK cell therapy combined with atezolizumab. Innovative approaches include engineering NK cells with multivalent galectin-3 binding polymers to mechanically reinforce immunological synapses with target tumor cells, enhancing their cytotoxic capacity. Research has identified compounds that modulate NK cell activity for pancreatic cancer treatment, addressing this highly aggressive malignancy's limited therapeutic options. Additional studies characterize NK cell dysfunction in aging, revealing declining per-cell cytotoxicity with age. Genetic factors including killer-cell immunoglobulin-like receptors and HLA class I molecules regulate antiviral and antitumor responses, particularly relevant in Epstein-Barr virus-associated nasopharyngeal carcinoma. These developments address critical gaps in cancer immunotherapy by leveraging NK cells' natural cytotoxic capabilities to overcome immune evasion and metastatic disease progression.

Glioblastoma multiforme remains one of the most lethal brain cancers, with dismal survival rates despite surgery, radiotherapy, and temozolomide chemotherapy. The primary challenge involves the blood-brain barrier and dense extracellular matrix, which prevent cytotoxic drugs from penetrating tumor cores. Researchers developed innovative ferritin nanomotors to overcome these barriers through a biomimetic nanotechnology platform combining self-propelling catalytic engines with active tumor infiltration capabilities. The nanomotors utilize heavy-chain ferritin nanocages loaded with catalytic cerium oxide cores, architecture that enables receptor-mediated transcytosis across brain capillaries and deep parenchymal infiltration into previously inaccessible tumor niches. Unlike conventional passive chemotherapy dependent on diffusion, these autonomous nanomotors navigate toward biochemical signatures within the tumor microenvironment, transforming ineffective molecular diffusion into targeted, force-driven therapeutic distribution. Since ferritin is a naturally occurring, biocompatible iron-storage protein found in human physiology, the platform exhibits negligible systemic toxicity. This innovative approach addresses critical treatment failures caused by drug accumulation only at tumor margins while invasive cells escape, ultimately triggering fatal recurrence.

Esophageal carcinoma remains a highly lethal malignancy with five-year survival rates of only 15-25% in advanced stages, despite advances in immunotherapy including immune checkpoint inhibitors and antibody-based therapies. This comprehensive review by researchers from Jilin University and Yale University addresses the critical challenge of immunotherapy resistance, which affects the majority of patients. The study demonstrates that the tumor microenvironment—comprising immune cells, stromal cells, and extracellular matrix—drives immune resistance through suppressive networks that impair cytotoxic immunity and enable tumor progression. The researchers dissect the cellular and molecular mechanisms underlying TME-driven immune resistance in esophageal carcinoma and evaluate multiple therapeutic strategies to overcome treatment failure. These approaches include TME-targeted therapy, metabolic modulation, photodynamic therapy, and mechanism-guided combination approaches. By reframing immunotherapy resistance as a tumor microenvironment-driven process rather than purely tumor-intrinsic, the work emphasizes the necessity of simultaneously targeting malignant cells and their immunosuppressive niche. Understanding TME heterogeneity and its dynamic evolution is essential for converting resistant esophageal carcinoma into an immunotherapy-responsive disease and enabling precision-guided combination strategies.

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.