bims-carter Biomed News
on CAR-T Therapies
Issue of 2025–10–12
forty-five papers selected by
Luca Bolliger, lxBio
  1. Recent advances in adoptive cell therapy for cancer immunotherapy.
  2. CAR-based cell therapy for autoimmune diseases.
  3. Clinical potential of CAR T cell-derived extracellular vesicles (CAR-EVs) in cancer therapy: a cell-free approach.
  4. Mechanistic data-informed multiscale quantitative systems pharmacology modeling framework enables the clinical translation and efficacy assessment of CAR-T therapy in solid tumors.
  5. Regulatory T cell therapy for xenotransplantation, what perspectives?
  6. Stem cell boost for immune effector cell associated hematotoxicity in multiple myeloma: minimizing long-term complications and expanding post CAR T-cell therapy relapse options.
  7. CAR T cell therapy for meningioma: mesothelin emerges as a novel promising target.
  8. Cellular Therapies in Transplantation - Regulatory T Cell Therapies and Virus Specific Therapies.
  9. Innate Immune Cells in Chimeric Antigen Receptor Therapy.
  10. Overcoming Barriers to Commercially Pre-Viable Gene and Cell Therapies for Rare and Ultra-Rare Diseases.
  11. B7-H3 in the tumor microenvironment: Implications for CAR T cell therapy in pediatric solid tumors.
  12. Chimeric antigen receptor-based cell therapy for treating urological tumors.
  13. Key considerations for advancing chimeric antigen receptor (CAR) T-cell therapy for systemic lupus erythematosus (SLE): a multi-partner/disciplinary working group perspective.
  14. How could γδ T cells change the treatment landscape for colorectal cancers?
  15. The physiological and pharmaceutical roles of MCTs and other ingredients in intravenous emulsions containing omega-3 enriched fish oil designed to mitigate cytokine release syndrome.
  16. Fine tuning towards the next generation of engineered T cells.
  17. Novel therapies in treatments of SLE.
  18. Fine-tuning signal strength in CD5 CAR-NK cells for targeted T cell cancer therapy.
  19. Predictive Factors and Baseline Risk Stratification for CAR-T Cell Therapy-Related Cardiovascular Toxicity.
  20. Comparison of regional differences in safety and efficacy of CAR-T therapy for hematologic malignancies in a real-world setting: a systematic review and meta-analysis.
  21. Enhancing Chimeric Antigen Receptor-Extracellular Vesicles (CAR-EV) Technology: The Future of Cancer Therapy.
  22. Navigating through regulatory frameworks for digital therapeutics and biomarkers.
  23. Enhanced solid tumor cell targeting by a neoepitope-encoding oncolytic measles virus combined with CAR therapy.
  24. CD19-directed chimeric antigen receptor T-cell therapy for relapsed or refractory diffuse large B-cell lymphoma: lessons learned from clinical trials and real world evidence.
  25. Physiologically Based Pharmacokinetic Modeling and Simulation in Regulatory Review: US FDA CBER Experience and Perspectives.
  26. Nanotechnology Meets the Tumor Microenvironment: Unlocking New Horizons in Cancer Therapy.
  27. The promise of immunotherapy for central nervous system tumours.
  28. The Role of Butyric Acid and Microorganisms in Chronic Inflammatory Diseases and Microbiome-Based Therapeutics.
  29. Research hotspots and trends in tumor vaccine adjuvants: A bibliometric analysis from 2010 to 2024.
  30. The Role of Immune Checkpoint Inhibitors in Cancer Therapy: Mechanism and Therapeutic Advances.
  31. Cost Assessment of Pediatric Haploidentical Hematopoietic Stem Cell Transplantation.
  32. Gut microbiota: a promising new target in immune tolerance.
  33. Selective HLA knockdown and PD-L1 expression prevent allogeneic CAR-NK cell rejection and enhance safety and anti-tumor responses in xenograft mice.
  34. Pediatric Applications of Digital Therapeutics: Clinical Evidence and Implementation Landscape.
  35. Anti-CD19 CAR T-Cell Therapy in Advanced Stiff-Person Syndrome and Concomitant Myasthenia Gravis.
  36. A review of safe and effective pharmacotherapies for Pediatric and neonatal septic shock.
  37. Targeting mTOR Kinase for Cancer Treatment: A Comprehensive Review With Clinical Insights.
  38. Decoding ferroptosis for cancer therapy.
  39. Ageing and remyelination failure in people with multiple sclerosis.
  40. Immune repertoire profiling and T cell dysregulation in Peripheral Blood Mononuclear Cells of Type 2 diabetic patients.
  41. Claudin 6 is a suitable target for CAR T-cell therapy in atypical teratoid/rhabdoid brain tumors and other pediatric solid tumors.
  42. Modulation of humoral immunity by γδ T cells: A potential adjuvant strategy for vaccination.
  43. Nanozyme-driven remodeling of the immune microenvironment: from catalytic therapy to precise immune regulation.
  44. Therapeutic extracellular vesicles as a cornerstone of medicine in the next decade with gerontological focus.
  45. Microbiome: Friend or Friendly Foe.
  1. Front Immunol. 2025 ;16 1665488
    Recent advances in adoptive cell therapy for cancer immunotherapy.
    Jiameng Qian, Yuhua Liu.
      Adoptive cell therapy (ACT), a key direction in tumor immunotherapy, has achieved remarkable progress in recent years. This paper systematically reviews the current status and future trends of ACT, covering lymphokine-activated killer cells (LAK), tumor-infiltrating lymphocytes (TIL), cytokine-induced killer cells (CIK), dendritic cells (DC), T cell receptor-modified T cells (TCR-T), chimeric antigen receptor T cells (CAR-T), natural killer (NK) cells, chimeric antigen receptor-modified NK cells (CAR-NK), and the emerging CAR-M. The paper focuses on emerging technological approaches, including universal CAR structural optimization, iPSC-derived cell products, multifunctional CAR design, and AI-assisted antigen screening. It also compares differences among various cell therapies in antigen specificity, efficacy persistence, safety, and clinical application challenges. The core contribution of this paper lies in synthesizing recent research advances to propose strategies for addressing tumor heterogeneity, antigen escape, cell persistence, and therapeutic safety in ACT. This provides a reference for future personalized and precision cell therapy approaches.
    Keywords:  CAR-M; CAR-NK; iPSC-derived cells; macrophage engineering; next-generation ACT
    DOI:  https://doi.org/10.3389/fimmu.2025.1665488
  2. Front Immunol. 2025 ;16 1613622
    CAR-based cell therapy for autoimmune diseases.
    Xiu Li, Chao He, Ke Wang, Guo-Ying Xu, Ya-Chao Xie, Xin-Yu Ying.
      Chimeric antigen receptor (CAR)-based cell therapies, initially designed for oncology, are rapidly advancing as a novel and highly targeted approach for the treatment of autoimmune diseases (AIDs). By harnessing engineered immune cells to eliminate autoreactive immune components or restore immune homeostasis, CAR-based strategies offer new avenues beyond conventional immunosuppression. In this review, we summarize current applications of CAR-T cells in autoimmune diseases, and discuss emerging approaches including CAR-Tregs, chimeric autoantibody receptor T (CAAR-T) cells, CAR-NK cells, and CAR-macrophages. We also describe advances in CAR design, including antigen selection, co-stimulatory domains, and safety control mechanisms, which are critical for improving therapeutic precision and reducing side effects. In addition, we highlight the role of synthetic biology in enabling more flexible and controllable CAR functions. Finally, we discuss the main challenges facing clinical translation, such as antigen specificity, long-term persistence, and manufacturing feasibility. These developments collectively support the potential of CAR-based therapies as a next-generation option for autoimmune disease treatment.
    Keywords:  CAR-T cell; autoimmune disease; cell therapy; chimeric antigen receptor; synthetic biology
    DOI:  https://doi.org/10.3389/fimmu.2025.1613622
  3. Ther Deliv. 2025 Oct 05. 1-19
    Clinical potential of CAR T cell-derived extracellular vesicles (CAR-EVs) in cancer therapy: a cell-free approach.
    Vaijayanti Kale, Ganesh Ingavle.
      Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary cancer treatment, but it has severe side effects. Extracellular vesicles (EVs), nanovesicles released by CAR T cells, known as CAR T-cell-derived EVs (CAR-EVs), are a potential alternative owing to their role in intercellular communication. This review comprehensively explores the clinical potential of CAR-EVs for cancer therapy, starting with their biogenesis and cargo, which include unique therapeutic molecules. It reviews the mechanisms underlying CAR-EV-mediated anticancer effects and presents preclinical evidence demonstrating efficacy across various cancers, including hematological malignancies and solid tumors. The review further discusses preclinical data and advantages over existing CAR T-cell therapies, emphasizing the need for future clinical studies to assess the safety and efficacy of CAR-EVs in cancer patients. This review also summarizes preliminary findings and challenges, proposing strategies to improve EV targeting and cargo delivery. Additionally, this review highlights unexplored aspects of EV biology in the context of CAR T-cell therapies. In conclusion, CAR-EVs offer a viable option for cancer therapy, with potential advantages over conventional CAR T-cell therapies. However, future research is needed to optimize manufacturing, distribution, and clinical application for achieve maximum therapeutic efficacy and favorable patient outcomes.
    Keywords:  CAR-T cell therapy; CAR-T-cell-derived extracellular vesicles (CAR-EVs); cancer treatment; cell-free therapy
    DOI:  https://doi.org/10.1080/20415990.2025.2569298
  4. J Immunother Cancer. 2025 Oct 09. pii: e012331. [Epub ahead of print]13(10):
    Mechanistic data-informed multiscale quantitative systems pharmacology modeling framework enables the clinical translation and efficacy assessment of CAR-T therapy in solid tumors.
    Siyuan Yang, Wenjie Wang, Qi Rao, Yiyang Xu, Sujie Zhang, Yuchen Qu, Qiuchuan Zhuang, Jie Mao, Laura Sun, Dong Geng, Da Xu, Chen Zhao.
       BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapy represents an innovative and potentially revolutionary modality in cancer treatment. Despite their great success in treating blood cancers, CAR-T therapies exhibit significantly lower effectiveness in treating solid tumors. Moreover, the preclinical-to-clinical translation of CAR-T therapies targeting solid tumors is still a challenging task because of their unique "live cell" nature and the substantial variability in patients' pathophysiology.
    METHODS: We have developed a multiscale quantitative systems pharmacology (QSP) model to facilitate the clinical translation of CAR-T therapies in solid tumors. Our mechanistic modeling framework integrates the essential biological features that impact CAR-T cell fate and antitumor cytotoxicity, from cell-level CAR-antigen interaction and activation, to in vivo CAR-T biodistribution, proliferation and phenotype transition, and finally to clinical-level patient tumor heterogeneity and response variability. This modeling framework has been calibrated and validated by multimodal experimental data including published preclinical and clinical data of various CAR-T products and original preclinical data of a novel claudin18.2-targeted CAR-T product LB1908.
    RESULTS: We demonstrated the general utility of this framework in facilitating clinical translation and characterizing the paired cellular kinetics-cytotoxicity response of different antigen-targeting solid tumor CAR-T cell therapies. As an example, we generated model-based virtual patients and prospectively simulated the response to claudin18.2-targeted CAR-T therapies under different dosing strategies, including step-fractionated dosing and convenient flat dose-based regimens, to inform future clinical trial implementation.
    CONCLUSIONS: Our translational QSP platform offers an innovative pathway to integrate multiscale knowledge and inform clinical decision-making of novel solid tumor-targeting CAR-T therapies.
    Keywords:  Adoptive cell therapy - ACT; Chimeric antigen receptor - CAR; Pharmacodynamics - PD; Solid tumor; T cell
    DOI:  https://doi.org/10.1136/jitc-2025-012331
  5. Front Immunol. 2025 ;16 1685682
    Regulatory T cell therapy for xenotransplantation, what perspectives?
    Raphaël Porret, Erica Lana, Antonio Mancarella, Philippe Guillaume, Manuel Pascual, Raphael P H Meier, Jonathan S Bromberg, Muhammad M Mohiuddin, Leo H Buhler, Qizhi Tang, Yannick D Muller.
      Xenotransplantation has experienced major clinical advancements over the past three years. Yet, despite potent immunosuppressive regimens combining B-cell depleting therapies, T cell activation blockade, complement inhibition, and high-dose steroids, signs of antibody-mediated and cellular rejection were seen in the few pig-to human heart and kidney xenotransplants. Considering the recent success of chimeric antigen receptor T cell therapies in severe refractory autoimmune diseases, there are windows for opportunities to develop novel approaches to reduce the burden of immunosuppression. In this line, regulatory T cell (Treg) therapy is an attractive strategy, as Tregs could be genetically modified to recognize pig organs. In this brief review, we summarize the lessons learned from Tregs therapies in allotransplantation, update on the recent development in Treg research for xenotransplantation, and discuss future perspectives of humanizing pigs with human leukocyte antigens to promote tolerance using engineered Tregs.
    Keywords:  cell therapy; chimeric antigen receptor; genetic engineering; regulatory T cells; xenograft tolerance; xenotransplantation
    DOI:  https://doi.org/10.3389/fimmu.2025.1685682
  6. Expert Rev Hematol. 2025 Oct 09. 1-7
    Stem cell boost for immune effector cell associated hematotoxicity in multiple myeloma: minimizing long-term complications and expanding post CAR T-cell therapy relapse options.
    Meera Mohan, Carolina Schinke.
       INTRODUCTION: Cytopenia is one of the most common adverse events after BCMA chimeric antigen receptor (CAR) T cell therapy in the treatment of relapsed multiple myeloma (MM). The term Immune Effector Cell Associated Hematotoxicity (ICAHT) was coined to describe the unique hematological toxicities following novel CAR T cell therapies. The management of prolonged ICAHT ( > 30 days) is quite challenging, and patients have high incidences of infections, require prolonged transfusion support and have an increased non-relapse mortality. Stem cell boost (SCB) leads to prompt and durable count recovery and can minimize long-term complications while enabling therapeutic options in the post CAR T-cell therapy relapse setting.
    AREAS COVERED: Herein we review current data on ICAHT, determine how SCB can lead to improved outcomes, and offer a view on future applications of SCB. The database 'pubmed' was searched for the terms 'CAR-T,' 'ICAHT', and 'Stem Cell', and results as well as selected citations were used for the present study.
    EXPERT OPINION: SCB for prolonged ICAHT improves morbidity and potentially mortality. Future use of SCB will depend on the long-term outcomes of CAR-T cell therapy in earlier treatment lines. For patients with high likelihood of ICAHT, prophylactive stem cell collection should be considered.
    Keywords:  CAR-T cell therapy; ICAHT; Multiple myeloma; cytopenia; stem cell boost; stem cell infusion
    DOI:  https://doi.org/10.1080/17474086.2025.2570335
  7. Neuro Oncol. 2025 Oct 11. pii: noaf240. [Epub ahead of print]
    CAR T cell therapy for meningioma: mesothelin emerges as a novel promising target.
    Denis Migliorini.
      
    DOI:  https://doi.org/10.1093/neuonc/noaf240
  8. Curr Transplant Rep. 2025 Dec;12(1):
    Cellular Therapies in Transplantation - Regulatory T Cell Therapies and Virus Specific Therapies.
    Zein Alabdin Hannouneh, Massini Merzkani, Chyi-Song Hsieh, Naoka Murakami.
       Purpose of Review: Cellular therapies have shown great promise in enhancing immune tolerance and managing opportunistic infections in transplant recipients. This review explores the latest advancements in regulatory T cell (Treg) and virus-specific T cell (VST) therapies in solid organ transplantation.
    Recent Findings: Treg-based therapies, including polyclonal Tregs, donor antigen-reactive Tregs (darTregs), and chimeric antigen receptor Tregs (CAR-Tregs) are being studied to minimize conventional, systemic immunosuppression while preventing graft rejection. Clinical trials demonstrated the safety and feasibility of ex vivo-expanded Tregs in kidney and liver transplantation, supporting reduced rejection rates and lower infection risks. The clinical applicability of CAR-T cell therapies extends to autoimmune diseases. Additionally, VSTs targeting BK virus, cytomegalovirus, Epstein-Barr virus, and adenovirus offer a novel approach for refractory viral infections in transplant recipients. Advances in third-party, "off-the-shelf" and multi-VSTs allow faster availability and standardized, scalable manufacturing compared to conventional VSTs.
    Summary: By reducing dependence on conventional immunosuppression, cellular therapies provide a promising approach in transplantation. To establish their role in clinical transplantation, further research is needed to optimize dosing and manufacture, improve antigen specificity, and address long-term safety concerns.
    Keywords:  Cellular therapy; Regulatory T cell; Tolerance; Virus-specific T cell therapy
    DOI:  https://doi.org/10.1007/s40472-025-00489-1
  9. Mol Ther. 2025 Oct 06. pii: S1525-0016(25)00824-X. [Epub ahead of print]
    Innate Immune Cells in Chimeric Antigen Receptor Therapy.
    Marius Jassaud, Lydia Ziane-Chaouche, Marie Duhamel, Michel Salzet.
      Chimeric antigen receptor (CAR) therapies have revolutionized cancer treatment, particularly with the success of CAR-T cells in hematologic malignancies. However, their application to solid tumors remains limited by major challenges, including cytokine release syndrome (CRS), neurotoxicity, poor tumor infiltration, antigen heterogeneity, and high manufacturing costs. These limitations have prompted growing interest in alternative immune effector cells. Innate immune cells - such as natural killer (NK) cells, macrophages, invariant natural killer T (iNKT) cells, gamma delta (γδ) T cells, dendritic cells (DCs) and neutrophils - offer distinct advantages. They are associated with a lower risk of graft-versus-host disease (GvHD), possess intrinsic tumor-homing and cytotoxic properties, and are suitable for off-the-shelf therapeutic platforms. This review explores the biological rationale and clinical potential of CAR-engineered innate immune cells, highlighting key findings from preclinical and clinical studies. Finally, we discuss combinatorial strategies and future directions that could shape the next generation of CAR-based therapies for solid tumors.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.10.003
  10. Mol Ther. 2025 Oct 04. pii: S1525-0016(25)00820-2. [Epub ahead of print]
    Overcoming Barriers to Commercially Pre-Viable Gene and Cell Therapies for Rare and Ultra-Rare Diseases.
    David Barrett, Paula M Cannon, Federico Mingozzi, Matthew Porteus, Isabelle Rivière, Terence R Flotte.
      Gene and cell therapies offer transformative potential for patients with rare and ultra-rare diseases. However, many treatments stall despite demonstration of safety and efficacy in pre-clinical studies and early-stage clinical trials. This market failure creates a barrier where otherwise successful therapies are unable to reach patients due to commercial non-viability. In March 2025, ASGCT held a workshop, "Establishing and Maintaining Access to Gene and Cell Therapy for Rare and Ultrarare Diseases," focusing on developing actionable paths forward to ensure that successful gene therapies reach patients regardless of commercial viability. The field faces ongoing and deep-seated challenges; addressing them will require coordinated action across private companies, regulatory agencies, and non-profit organizations to explore non-traditional business models. During the workshop and described here, ASGCT reviewed a matrix of solutions encompassing regulatory innovations, manufacturing efficiencies, financial modeling, and patient-focused frameworks to ensure that efficacious gene and cell therapies reach the patients who need them. Strategies included the creation of a temporary repository for deprioritized gene and cell therapy programs offering support while working to identify new sponsors to continue clinical trials and the creation of a consortium of developers focused on accelerating timelines and reducing costs.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.09.049
  11. Cancer Metastasis Rev. 2025 Oct 11. 44(4): 77
    B7-H3 in the tumor microenvironment: Implications for CAR T cell therapy in pediatric solid tumors.
    Lena Jansen, Judith Wienke, Ronja Molkenbur, Claudia Rossig, Ramona Meissner.
      B7 homolog 3 (B7-H3, CD276) has emerged as a promising target for chimeric antigen receptor (CAR) T cell therapy, with limited expression in normal tissues and high level cell-surface expression across various tumor types. Clinical studies are ongoing, with a focus on pediatric cancers. As an immune checkpoint molecule of the B7-CD28 family, B7-H3 has a proposed immune-modulatory role, though the precise nature of B7-H3-mediated cell interactions and functional contributions to immune responses are contradictory and likely context-dependent. Within tumors, B7-H3 is expressed also on non-tumor cell types in the tumor microenvironment (TME), including myeloid immune cells, endothelial cells of abnormal vasculature and cancer-associated fibroblasts. Consequently, CAR T cells directed against B7-H3 will not only target tumor cells but also components of the TME, which will affect the nature and outcome of B7-H3-targeted therapeutic immune responses. Here we review the expression of B7-H3 protein in pediatric solid tumors and in various cell types known to infiltrate the TME of solid tumors. On this background, we discuss the potential of B7-H3-targeted CAR T cells to reshape the TME and the key challenges and future directions to improve B7-H3-targeted CAR T cell therapy for pediatric patients with solid cancers.
    Keywords:  B7-H3; CAR T cells; CD276; Immune checkpoints; Pediatric solid cancers; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s10555-025-10294-y
  12. Curr Urol. 2025 Nov;19(6): 363-375
    Chimeric antigen receptor-based cell therapy for treating urological tumors.
    Huidi Tang, Linpei Guo, Wen Zhang, Dongqi Tang.
      Urological tumors represent a significant global health challenge, with conventional therapies often proving insufficient to control disease progression. Recent breakthroughs in cellular immunotherapy, particularly in chimeric antigen receptor (CAR)-T cell, CAR-natural killer cell, and CAR-macrophage therapies, have demonstrated remarkable potential for treating these malignancies. Ongoing research is actively refining CAR-based strategies to enhance their precision in targeting tumor-associated antigens. This review comprehensively summarizes the applications of CAR cell therapy in the following 3 major urological tumors: renal cell carcinoma, bladder cancer, and prostate cancer. Furthermore, we analyzed the current advantages and limitations of these approaches and propose potential strategies for optimization focused on CAR-T cells. This review will provide future directions in this field and contribute to the development of more effective treatments for patients with urological cancer.
    Keywords:  CAR cell therapy; Chimeric antigen receptor; Clinical application; Urological tumors
    DOI:  https://doi.org/10.1097/CU9.0000000000000305
  13. RMD Open. 2025 Oct 05. pii: e005866. [Epub ahead of print]11(4):
    Key considerations for advancing chimeric antigen receptor (CAR) T-cell therapy for systemic lupus erythematosus (SLE): a multi-partner/disciplinary working group perspective.
    Lupus ABC CAR T Working Group
      Early data have shown the potential of chimeric antigen receptor (CAR) T-cell therapies to expand the therapeutic landscape in systemic lupus erythematosus (SLE). While many CAR T-cell therapy learnings can be drawn from the experience of this modality in oncology, key questions remain regarding clinical development considerations unique to lupus. To assess and discuss these issues, the Lupus Accelerating Breakthroughs Consortium, a public-private partnership, convened a multi-partner working group to collect the diverse perspectives of academics/clinicians (including rheumatologists and oncologists), industry representatives (including SLE as well as CAR T-cell clinical development experts), regulators and people living with lupus on this potentially ground-breaking therapy. The working group considered the risk/benefit considerations for eligibility criteria in lupus, early-phase dosing and dose-limiting toxicity challenges, incorporation of comparator arms in late-phase registrational trial design, SLE-specific issues in conditioning therapy and immune monitoring and the limitations of SLE pre-clinical models for studying cell therapies. The key future 'calls to action' for the field include the need for well-defined severity/refractoriness-based eligibility criteria, the need for long-term monitoring infrastructure and the need for educational and logistical support for rheumatologists and patients.
    Keywords:  Biological Therapy; Clinical Trial; Lupus Erythematosus, Systemic; Lupus Nephritis; T-Lymphocytes
    DOI:  https://doi.org/10.1136/rmdopen-2025-005866
  14. Immunotherapy. 2025 Oct 11. 1-4
    How could γδ T cells change the treatment landscape for colorectal cancers?
    Rafael Blanco-Domínguez, Sofia Mensurado.
      
    Keywords:  CAR-T; Colorectal cancer; cell therapy; immune checkpoint blockade; immunotherapy; γδ T cells
    DOI:  https://doi.org/10.1080/1750743X.2025.2572962
  15. Front Pharmacol. 2025 ;16 1673290
    The physiological and pharmaceutical roles of MCTs and other ingredients in intravenous emulsions containing omega-3 enriched fish oil designed to mitigate cytokine release syndrome.
    David F Driscoll, Bruce R Bistrian.
      Cytokine release syndrome (CRS) is a serious adverse effect often seen following the administration of cancer immunotherapy, particularly with chimeric antigen receptor (CAR) T cell therapy. Recently, we proposed the administration of precise amounts of the primary active ingredients found in fish oil (EPA + DHA) in combination with medium chain triglycerides (MCTs). Although there is a commercial injectable emulsion containing a refined-only fish oil, it is indicated as a nutritional supplement because it contains highly variable concentrations of the primary active ingredients (±50% of EPA + DHA). We suggested the application of a refined and enriched fish oil in order to provide the desired pharmacological doses according to the typical limits for drugs, i.e., EPA + DHA, within ±10% of the labeled amount. This tight tolerance is not achievable with "refined-only" fish oil indicated for nutrition support. The purpose of this review is to further describe the details of such a dosage form, with particular focus on other active ingredients in the proposed formulation. They play important roles in delivering a safe final product with multiple therapeutic targets for the acute systemic inflammatory response from CRS, as well as addressing chronic inflammation within the tumor microenvironment (TME).
    Keywords:  CAR T cell therapy; cytokine release syndrome; long chain triglycerides; medium chain triglycerides; omega-3 fatty acids
    DOI:  https://doi.org/10.3389/fphar.2025.1673290
  16. Nat Biomed Eng. 2025 Oct 10.
    Fine tuning towards the next generation of engineered T cells.
    Tham T Nguyen, Patrick Ho, Sarah Staudt, Celine Gregoire, Kai Ziegler-Martin, Megane Jassin, Alix Block, Michael Hudecek, J Joseph Melenhorst, Jo Caers, Maik Luu.
      Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in treating haematologic malignancies. However, the rise in clinical use has highlighted substantial challenges related to T cell- and tumour-intrinsic mechanisms. Additionally, the tumour microenvironment can render these treatments dysfunctional. Extensive attempts in the field are optimizing the key elements of CAR T cell products for therapy, including antigen specificity and affinity, metabolic fitness, phenotypic stability and manufacturing. Recent efforts in transcriptomic and epigenetic profiling, as well as high-throughput functional screening methods, have identified new classes of targets, binders and mechanisms to be exploited. Advances in gene editing and delivery offer opportunities to translate those strategies into clinical trials. Here we discuss the multifaceted exploration of CAR T cell engineering approaches and emerging directions, highlighting the available strategies that can be built on to create the next generation of cellular therapies.
    DOI:  https://doi.org/10.1038/s41551-025-01492-8
  17. Best Pract Res Clin Rheumatol. 2025 Oct 07. pii: S1521-6942(25)00069-5. [Epub ahead of print] 102101
    Novel therapies in treatments of SLE.
    Yoshiya Tanaka.
      Systemic lupus erythematosus (SLE) is an autoimmune disease that damages multiple organs. Glucocorticoids (GCs) have been a mainstay of the treatment of SLE, but it is strongly recommended to minimize GCs usage due to the toxicity of long-term use. Currently, development of molecular-targeted therapies based on pathological mechanisms is underway. Activation of B cells through T-B cell interaction play a central role in the pathogenesis, and treatments targeting B cells and co-stimulatory molecules are expected. In addition, many disease susceptibility genes are mediated in signaling by the innate immune mechanisms, such as dendritic cells involvement and cytokines production that stimulates acquired immunity, as well as kinases of intracellular signaling molecules that are described as targets. Furthermore, adoptive transfer of T cells engineered to target CD19 antigen by gene transfer of chimeric antigen receptor and by T cell engagers that recruit T cells and induce B cell cytotoxicity gather attention.
    Keywords:  Biological agent; CAR-T therapy; Lupus nephritis; Systemic lupus erythematosus; Targeted therapy
    DOI:  https://doi.org/10.1016/j.berh.2025.102101
  18. Front Immunol. 2025 ;16 1674376
    Fine-tuning signal strength in CD5 CAR-NK cells for targeted T cell cancer therapy.
    Seona Jo, Yu Bin Lee, Seok Min Kim, Soo Yun Lee, Myeongjin Choi, Mi-Lang Kyun, Seo Yule Jeong, Sunyoung Lee, Ji Hyun Kim, Yoonji Kim, Yu Jung Kim, Sora Park, Kyoung-Sik Moon, Tae-Don Kim.
       Introduction: T cell hematological malignancies are aggressive blood cancers that remain challenging despite various treatments. Current chimeric antigen receptor (CAR)-T and natural killer (NK) therapies show potential but struggle with nonselective elimination during tumor targeting. Since CAR signal strength is determined by the single-chain variable fragment (scFv) and CAR expression levels, fine-tuning these parameters enables selective recognition of malignant cells while preserving normal cells. Here, we aimed to develop optimized CD5 CAR-NK cells (OptiCAR-NK) to achieve potent anti-tumor activity with minimized off-tumor toxicity.
    Methods: We engineered CD5 CAR-NK cells with different scFv and CAR expression levels. CAR expression was modulated by single-cell isolation and mRNA transfection to assess activity against both malignant and normal T cells in vitro. Therapeutic efficacy and safety were further validated in xenograft and humanized mouse models.
    Results: Optimization of scFv and CAR expression levels (OptiCAR-NK) enabled selective recognition of CD5+ malignant T cells while maintaining strong anti-tumor activity with minimal toxicity. Mechanistic analysis revealed that NK cells' innate ability to discriminate malignant from normal T cells depends on fine-tuned CAR signal strength and endogenous ligands on target cells.
    Discussion: Optimized modulation of scFv and CAR expression is crucial for designing a CAR that achieves high anti-cancer efficacy and is safe in normal cells. Our results suggest a promising avenue for optimized CD5 CAR-NK cell therapy to manage T cell malignancies while minimizing off-tumor effects.
    Keywords:  CAR expression; CAR-NK; CD5; T cell malignancies; on-target off-tumor toxicity; scFv
    DOI:  https://doi.org/10.3389/fimmu.2025.1674376
  19. Eur J Haematol. 2025 Oct 07.
    Predictive Factors and Baseline Risk Stratification for CAR-T Cell Therapy-Related Cardiovascular Toxicity.
    Dimitrios Farmakis, Konstantinos Karampinos, Raul Cordoba, Teresa López-Fernández, Gerasimos Filippatos.
       AIMS: Baseline cardiovascular (CV) risk stratification is an essential component in managing patients undergoing potential cardiotoxic anticancer therapies. Chimeric antigen receptor (CAR)-T cell therapy, a groundbreaking treatment for hematologic malignancies, is associated with a non-negligible risk of cardiovascular adverse events (CVAE). This study aimed to identify predictors of CAR-T cell-related CVAE and to develop a corresponding risk stratification score.
    METHODS: We conducted a meta-analysis of studies comparing baseline clinical, biomarker, echocardiographic findings, and pharmaceutical treatments between patients who developed CAR-T cell-related CVAE and those who did not. We subsequently used the pooled relative risks (RR) of significant predictors to construct a risk stratification score.
    RESULTS: We identified 12 relevant studies encompassing a total of 1354 patients with haematologic malignancies, the majority of which were treated with CD19-directed CAR-T cell therapy, of whom 228 (16.8%) developed CVAE. Significant predictors of CAR-T cell-related CVAE included coronary artery disease [RR = 2.27 (95% confidence interval, 1.46-3.51)], hyperlipidaemia [1.57 (1.14-2.15)], diabetes [1.59 (1.13-2.24)], hypertension [1.45 (1.18-1.77)], atrial fibrillation [2.42 (1.51-3.88)], heart failure [2.74 (1.62-4.61)], and smoking [1.40 (1.10-1.79)]. The resulting risk prediction score, incorporating the above seven factors, named CART-7, ranges from 0 to 33, with a score of 0-8 indicating low risk, 9-17 moderate risk, 18-25 high risk, and 26-33 very high risk.
    CONCLUSION: Seven baseline CV conditions were significantly associated with CAR-T cell-related CVAE. Further validation of the resulting CART-7 score is warranted to support its clinical use in baseline CV risk stratification for patients undergoing CAR-T cell therapy.
    Keywords:  CAR‐T cell; cancer; cardiotoxicity; haematological malignancies; meta‐analysis; risk stratification
    DOI:  https://doi.org/10.1111/ejh.70040
  20. Crit Rev Oncol Hematol. 2025 Oct 08. pii: S1040-8428(25)00357-9. [Epub ahead of print] 104969
    Comparison of regional differences in safety and efficacy of CAR-T therapy for hematologic malignancies in a real-world setting: a systematic review and meta-analysis.
    Zhihan Chen, Wenjng Luo, Yun Kang, Jia Xu, Chenggong Li, Xindi Wang, Yinqiang Zhang, Qiaolin Liu, Heng Mei.
       BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment landscape of patients with hematologic malignancies. Nevertheless, geographic regions may lead to various outcomes, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), overall remission rate (ORR), and complete remission rate (CRR). However, the related evidence of real-world studies and systematic analysis remains limited.
    OBJECTIVE: This meta-analysis aims to compare the real-world incidence of CRS and ICANS, as well as therapeutic outcomes ORR/CRR, in patients with hematologic malignancy treated with CAR-T therapy across different regions.
    METHODS: A systematic literature search was conducted in Pubmed, Embase, and Cochrane Library databases published up to February 2025. Subgroup analyses were performed based on geographic regions and other factors.
    RESULTS: Seventy corhorts from 4 different regions comprising 9,233 patients were included. North America exhibited the highest incidence of CRS at 83%, surpassing Europe (82%) and Asia (80%) significantly (p<0.01). However, no significant regional differences existed in grade ≥3 CRS. The incidence of ICANS was notably higher in North America (39%) compared to Europe (32%) and Asia (21%; p=0.08), with grade ≥3 ICANS also more prevalent in North America (16%) than in Europe (9%) and Asia (2%; p<0.01). Efficacy did not vary across different regions.
    CONCLUSION: Patients in North America possessing elevated rates of CRS and grade ≥3 ICANS. The results provide valuable insights to the adverse effects when treating patients with CAR-T cells across different regions in a real-world setting.
    Keywords:  CAR-T therapy; CRS; ICANS; hematologic malignancies; real-world; regional differences
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.104969
  21. J Vis Exp. 2025 Sep 19.
    Enhancing Chimeric Antigen Receptor-Extracellular Vesicles (CAR-EV) Technology: The Future of Cancer Therapy.
    Kartini Asari, Sharenya Chelvaretnam, Kol Thida Mom, Sadman Bhuiyan, Quang Pham, Amirah Fitri, Carlos Palma, Mozhgan Shojaee, Ramin Khanabdali, Leearne Hinch, Gregory Rice.
      CAR cell therapies have significantly advanced personalized treatment for several hematological malignancies. Currently, seven CAR- cell products are approved by the Food and Drug Administration (FDA) and six by the European Medicines Agency (EMA) for treating lymphoma, multiple myeloma, and chronic lymphocytic leukemia. Several challenges and limitations remain, with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) being the most significant. Cell-free therapies, such as CAR-EVs, offer substantive advantages over their cellular counterparts. These include enhanced tumor infiltration and the potential for repeat administration while minimizing the risks of CRS, ICANS, and other adverse side effects. Additionally, the potency of CAR-EVs can be tuned by engineering the inclusion of cytotoxic agents and function-modifying ribonucleic acids (RNAs). Herein, we report on the development of a scalable CAR-EV platform for producing tunable CAR-EVs. This platform includes the engineering and pre-conditioning of EV producer cells (e.g., CAR-T and CAR-natural killer (CAR-NK) cells), isolation and enrichment of CAR-EVs using a Good Manufacturing Practice (GMP) grade ion-exchange chromatography (IEX) platform, fully automated high-throughput EV subpopulation analysis, and in vitro evaluation of CAR-EV functional cytotoxic activity. The platform has been validated using CAR-NK-EVs and CAR-T-EVs for both hematological and solid tumor cell lines. The CAR-EV platform represents a promising approach for the rapid development of off-the-shelf therapeutic CAR-EVs tailored to specific disease indications, with the potential to reduce adverse side effects associated with CAR-cell-based therapies.
    DOI:  https://doi.org/10.3791/68726
  22. Health Informatics J. 2025 Oct-Dec;31(4):31(4): 14604582251387656
    Navigating through regulatory frameworks for digital therapeutics and biomarkers.
    Cinja Koller, Marc Blanchard, Thomas Hügle.
      Background: Digital health technologies are often subject to regulatory requirements. Regulatory auditing processes are complex but necessary to guarantee quality, efficacy and safety of patients. Evolvements such as digitalized clinical trials, and digital biomarkers require a constant adaption of regulatory frameworks. Objective: This review aims to provide an overview on current regulations and standards for digital therapeutics and digital biomarkers, from technical development to market access. Methods: We conducted an unstructured literature review to identify the relevant guidelines, policies and standards for software based digital therapeutics and digital biomarkers. Results: The principal regulations governing software as a medical device are outlined in Chapter 21 of the Code of Federal Regulations by the US Food and Drug Administration, as well as the European Medical Device Regulation 2017/745. Regulatory pathways, such as the DiGA, are in the process of development, particularly for digital therapeutics, which fall within the purview of software as a medical device. Qualification of (digital) biomarkers is typically voluntary but can play a significant role in the development and approval of digital therapeutics. Conclusions: Fragmented, lacking and diverse regulations around digital biomarkers and digital therapeutics highlight the urge to harmonize and foster regulatory frameworks on an international level.
    Keywords:  CFR; EMA; FDA; MDR; digital biomarker; digital health; digital therapeutics; regulation; software as a medical device
    DOI:  https://doi.org/10.1177/14604582251387656
  23. Mol Ther Oncol. 2025 Dec 18. 33(4): 201043
    Enhanced solid tumor cell targeting by a neoepitope-encoding oncolytic measles virus combined with CAR therapy.
    Alexander Renner, Maximiliane S C Finkbeiner, Ferdinand V Haas, Anika Stahringer, Max Lindow, Nicolas Delaroque, Michael Szardenings, Stephan Fricke, Ulrike Koehl, Christine E Engeland, Dominik Schmiedel.
      Despite the success of cell therapy in treating hematological malignancies, the treatment of solid tumors remains challenging due to the tumor microenvironment (TME) and a lack of suitable antigens. To address this, we investigated a putative octapeptide neoepitope generated by proteolytic cleavage of the stress-induced protein MHC class I polypeptide-related sequence B (MICB). Antibodies developed via the hybridoma technique exhibited high affinity and specificity toward the octapeptide. Detection of the octapeptide was enhanced by inserting an α-helical linker before the transmembrane domain, improving accessibility on stably transduced cells. Two chimeric antigen receptor (CAR) constructs with differing single-chain variable fragment (scFv) chain orientations were expressed in primary T and natural killer (NK) cells, showing antigen-specific cytotoxicity, particularly when incorporating the rigid linker. Variations in sensitivity between CARs influenced killing efficacy and activation profiles. Oncolytic measles virus (MV) was used as a vector encoding the membrane-anchored octapeptide, selectively infecting tumor cells and enhancing CAR-T cell-mediated cytotoxicity. Combined use of CAR-T and (CAR-)NK cells demonstrated increased persistence of immune cells as well as potent and sustained antitumor effects following MV infection. This study underscores the potential of neoepitope-based CAR therapy for targeting solid tumor cells and highlights the potential synergistic effects of combining cell therapy with virotherapy for improved therapeutic outcomes.
    Keywords:  CAR-NK cell; CAR-T cell; MT: Regular Issue; cancer therapy; cell engineering; gene delivery; gene therapy; measles virus; oncolytic virus; solid tumor
    DOI:  https://doi.org/10.1016/j.omton.2025.201043
  24. Leuk Lymphoma. 2025 Oct 10. 1-13
    CD19-directed chimeric antigen receptor T-cell therapy for relapsed or refractory diffuse large B-cell lymphoma: lessons learned from clinical trials and real world evidence.
    Supriya Gupta, Veronika Bachanova.
      CD19-directed Chimeric Antigen Receptor T-Cell therapy has revolutionized treatment for relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL). Since the approval of axicabtagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel-CAR-T has offered high response rates and durable remissions for patients with limited options. Real-world data support its curative potential in 40-50% of patients. However, challenges remain, including toxicity management, individualized manufacturing, logistical complexity and access barriers. Over seven years of clinical experience have led to streamlined manufacturing and improved strategies for managing toxicities such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. These advances have expanded access and optimized delivery. Ongoing refinements in patient selection, and toxicity mitigation continue to improve outcomes. This review consolidates pivotal trial and real-world findings, addressing non-conforming products, outpatient administration, access barriers, and future directions. Emerging innovations in next-generation therapies and access strategies offer a roadmap for continued clinical and research progress.
    Keywords:  Lymphoma and Hodgkin disease; adoptive cellular therapies; immunotherapy; neoplasia
    DOI:  https://doi.org/10.1080/10428194.2025.2560082
  25. AAPS J. 2025 Oct 09. 27(6): 157
    Physiologically Based Pharmacokinetic Modeling and Simulation in Regulatory Review: US FDA CBER Experience and Perspectives.
    Million A Tegenge, Osman N Yogurtcu, Artur A Belov, Xiaofei Wang, Richard A Forshee.
      Physiologically based pharmacokinetic (PBPK) modeling has emerged as a valuable tool in model-informed drug development (MIDD). This approach enables the integration of diverse experimental data to predict pharmacokinetics (PK) and dosing regimens and facilitates understanding of mechanism of action (MoA) and pharmacodynamics (PD). In this article we provide a landscape analysis of PBPK submissions at the U.S. Food and Drug Administration, Center for Biologics Evaluation and Research (CBER). We summarize CBER's experience on PBPK modeling and simulation (M&S) for therapeutic proteins, cell and gene therapy products. We discuss specific case studies that illustrate the use of PBPK for dose selection of therapeutic proteins, highlight recent progress and provide our perspectives on potential application of PBPK for adeno-associated virus (AAV)-based gene therapies and messenger RNA (mRNA) therapeutics. For cell and gene therapy products, PBPK M&S is emerging as MIDD approaches to support clinical trial design, dose selection, predicting PK/PD, and facilitate quantitative understanding of safety and efficacy. As the field continues to evolve, PBPK modeling is well positioned to provide supportive evidence to facilitate the development of safe and effective biological products.
    Keywords:  AAV; Cell therapy; MIDD; MRNA; PBPK; Quantitative pharmacology
    DOI:  https://doi.org/10.1208/s12248-025-01155-1
  26. ACS Biomater Sci Eng. 2025 Oct 07.
    Nanotechnology Meets the Tumor Microenvironment: Unlocking New Horizons in Cancer Therapy.
    Pankaj Yadav, Amit K Yadav, Dhiraj Bhatia.
      The tumor microenvironment (TME) is a critical orchestrator of cancer progression, shaped not only by genetic mutations but also by dynamic factors such as acidic pH, dysregulated extracellular matrix (ECM), immunosuppressive cells, and cytokine networks. These elements collectively foster therapeutic resistance and metastasis, challenging conventional treatments. Nanotechnology has emerged as a transformative approach to dismantling TME barriers, enabling precise targeting and enhanced drug delivery. In addition, a key focus is overcoming ECM density and immunosuppression. For instance, ECM-degrading nanoparticles (NPs) loaded with hyaluronidase or collagenase improve drug penetration, while immune-modulating NPs reprogram macrophages from protumor (M2) to antitumor (M1) phenotypes. Complementing these strategies, advances in immune cell engineering, such as chimeric antigen receptor (CAR) T cells or natural killer (NK) cells, are synergized with NPs-delivered checkpoint inhibitors to amplify antitumor immunity. Additionally, pH-sensitive and enzyme-responsive NPs exploit TME-specific conditions for controlled drug release, minimizing systemic toxicity. Despite promising preclinical results, clinical translation faces hurdles. Challenges include optimizing NPs' biocompatibility, scalability, and long-term safety as well as addressing interpatient TME heterogeneity. Thus, this review explores innovative NPs designs engineered to navigate the TME complexity, including surface modifications with antibodies, folic acid, transferrin, peptides, and amino acids. These functionalized NPs improve tumor-specific targeting while evading immune clearance, thereby enhancing chemotherapeutic efficacy and reducing off-target effects. Moreover, this review evaluates current progress in NPs-based clinical trials targeting the TME and discusses emerging theranostic platforms that combine real-time imaging with therapy. By integration of multidisciplinary insights from materials science, immunology, and systems biology, nanotechnology holds immense potential to unlock personalized cancer therapies. Future research must prioritize scalable manufacturing and robust biomarker-driven approaches to realize this paradigm shift in oncology fully.
    Keywords:  cancer therapy; immune modulation; nanoparticles; surface modification; targeted drug delivery; tumor microenvironment
    DOI:  https://doi.org/10.1021/acsbiomaterials.5c01120
  27. Nat Rev Immunol. 2025 Oct 06.
    The promise of immunotherapy for central nervous system tumours.
    Jasia Mahdi, Vrunda Trivedi, Michelle Monje.
      The nervous and immune systems are intricately linked to one another through bi-directional crosstalk. Given the limited therapeutic options for aggressive and refractory central nervous system (CNS) tumours, immunotherapies are increasingly being explored as potential treatments for these malignancies. In this Review, we provide an overview of the nervous system-immune system connections that provide the basis for the use of immunotherapy to treat CNS tumours. We then summarize the outcomes from preclinical and clinical studies that have used immunotherapies, including chimeric antigen receptor T cell therapy, oncolytic viruses, cancer vaccines and immune-checkpoint inhibitors, for the treatment of primary CNS cancers such as high-grade gliomas, refractory embryonal brain tumours and primary CNS lymphomas. Finally, we review the neurological symptoms and syndromes that can arise with these immunotherapeutic approaches.
    DOI:  https://doi.org/10.1038/s41577-025-01227-5
  28. J Inflamm Res. 2025 ;18 13465-13487
    The Role of Butyric Acid and Microorganisms in Chronic Inflammatory Diseases and Microbiome-Based Therapeutics.
    Zhilin Liu, Yonghong Jiang, Qiuyue Fan, Sai Li, Yanni Wang.
      Butyric acid, produced by gut microbiota fermentation, has gained significant attention over the past decade. It shows strong therapeutic potential in both experimental and clinical treatments for inflammatory diseases across multiple systems. However, factors such as the host's environment, genetics, and microbial lineage transmission influence gut microecology and butyric acid metabolism, resulting in variable and sometimes opposing, therapeutic effects. Consequently, precise personalized medicine is essential for diseases related to microbes and butyric acid. This review first introduces the fundamentals of butyric acid, focusing on its immune mechanisms and its effects on early-life microbiota. It then summarizes how microbes and butyric acid contribute to the treatment of systemic inflammatory diseases (eg, autoimmune diseases (AIDs), asthma, metabolic syndrome) and discusses the concept of Microbial Precision Therapy (MPT). Understanding butyric acid provides deeper insight into managing inflammatory diseases and supports precise medication and personalized therapy. This approach may offer more effective and safer strategies for multi-system inflammatory disorders.
    Keywords:  butyric acid; inflammatory diseases; intestinal flora; microbial precision therapy
    DOI:  https://doi.org/10.2147/JIR.S540163
  29. Hum Vaccin Immunother. 2025 Dec;21(1): 2527450
    Research hotspots and trends in tumor vaccine adjuvants: A bibliometric analysis from 2010 to 2024.
    Lutian Gong, Wenping Lu, Lei Chang, Yongjia Cui, Siqing Zhao.
      Tumor vaccine adjuvants play a critical role in enhancing anti-tumor immune responses, and it is essential to summarize their research hotspots and future trends. This study retrieved and evaluated 6,177 publications on tumor vaccine adjuvants from the Web of Science Core Collection between 2010 and 2024. Most publications originated from the United States and China, with the Chinese Academy of Sciences being the most productive institution. George E. Peoples published 29 articles, and the journal Vaccine had the highest publication frequency. Keyword co-occurrence analysis reflects a research paradigm shift from theoretical exploration to delivery system optimization and clinical translation: earlier studies focused on fundamental immune mechanisms (e.g. "dendritic cell," "immune response," "antigen"), while recent research has turned toward translational technologies (e.g. "drug delivery," "nanoparticles"). Future studies may focus on optimizing delivery systems, exploring novel adjuvants, advancing clinical translation, and further elucidating the mechanisms by which adjuvants enhance immune responses.
    Keywords:  Bibliometric; CiteSpace; VOSviewer; adjuvant; hotspot; tumor vaccine
    DOI:  https://doi.org/10.1080/21645515.2025.2527450
  30. MedComm (2020). 2025 Oct;6(10): e70412
    The Role of Immune Checkpoint Inhibitors in Cancer Therapy: Mechanism and Therapeutic Advances.
    Hengyi Chen, Hongling Yang, Lu Guo, Qingxiang Sun.
      The rapid development of immune checkpoint inhibitors has fundamentally changed the landscape of cancer treatment. These agents restore T cell-mediated antitumor immune responses by targeting key immune checkpoint molecules, thereby suppressing or eliminating tumors. However, their clinical application still faces multiple challenges, mainly including efficacy heterogeneity, drug resistance, immune-related adverse events. Furthermore, there is still a lack of reliable biomarkers for predicting efficacy and toxicity. More critically, there is absence of precise predictive models that can systematically integrate multiomics features, dynamic tumor microenvironment evolution, and patient individual differences to comprehensively address the above issues. This review systematically summarizes the latest advancements in this field. The main contents include emerging targets like lymphocyte activation gene 3, T cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif domain, and mucin-domain-containing-3, combination strategies, and the current research status and limitations of various predictive biomarkers. Moreover, it focuses on the potential of microbiome regulation, metabolic reprogramming, and artificial intelligence-driven multiomics analysis technologies in achieving dynamic patient stratification and personalized treatment. By integrating the frontier research results and clinical insights, the review aims to provide a systematical theory framework and future directions for advancing precision immunotherapy.
    Keywords:  CTLA‐4; PD‐1/PD‐L1; combination therapy; drug resistance; immune checkpoint inhibitors; precision immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1002/mco2.70412
  31. Clinicoecon Outcomes Res. 2025 ;17 653-659
    Cost Assessment of Pediatric Haploidentical Hematopoietic Stem Cell Transplantation.
    Leila Achour, Ikram Fazaa, Chema Drira, Yosr Trabelsi, Monia Ouederni, Ines Fradi.
       Purpose: Evaluate the costs related to the pediatric haplo-SCT and adult and pediatric geno-SCT at the CNGMO in order to establish a tailored reimbursement package by the Tunisian Health Insurance Fund.
    Patients and Methods: This pharmaco-economic study compared the cost of pediatric haplo-SCT to adult and pediatric geno identical hematopoietic stem cell transplantation (geno-SCT) using the activity-based costing method. The cost assessment was conducted from the hospital's perspective and considered direct medical and non-medical costs.
    Results: The cost assessment indicated that pediatric patients incurred higher expenses than adult patients. Furthermore, haplo-SCT was more expensive than geno-SCT for pediatric patients. The conditioning regimens used before haplo-SCT are more intensive than other preparative regimens and typically require longer inpatient therefore resulting in more costs. Complications, such as infections during the early phase of neutropenia and late-onset issues following hematopoietic stem cell transplantation (HSCT), particularly graft-versus-host disease (GVHD) and cytomegalovirus (CMV) reactivation, significantly contribute to increased procedural costs.
    Conclusion: This study sets the standards for new specific packages for haplo-SCT and geno-SCT in pediatric patients.
    Keywords:  cost; haploidentical; pediatric; stem cell transplant
    DOI:  https://doi.org/10.2147/CEOR.S525645
  32. Front Immunol. 2025 ;16 1607388
    Gut microbiota: a promising new target in immune tolerance.
    Nourah Almansour, Fatema Al-Rashed, Khubaib Choudhry, Hend Alqaderi, Sardar Sindhu, Fahd Al-Mulla, Rasheed Ahmad.
      Gut microbiota research has highlighted its pivotal role in human health and disease. Its composition is shaped by diet, genetics, age, and environmental factors. When the balance of these microbes is disrupted (dysbiosis), it can contribute to health problems like metabolic, inflammatory, and mental disorders. The microbiota supports digestion, fermentation, and vitamin production, which are essential for overall health. The gut microbiota has emerged as a critical modulator of immune function, with increasing evidence highlighting its role in establishing and maintaining immune tolerance. Despite significant advances in understanding the interactions between the gut microbiome and immune system, gaps remain in the literature regarding the specific mechanisms through which microbiota influences immune tolerance. This review aims to address these knowledge gaps by synthesizing current research on the microbiota impact on immune tolerance, emphasizing key factors such as microbial diversity, metabolic byproducts, and the microbiota interaction with immune cells, specifically focusing on the role of microbial tryptophan metabolites in PD-1/PD-L1 tolerance. We also highlight critical areas for future research, including the identification of microbial species or strains that can modulate immune tolerance, the influence of diet and environmental factors on microbiota composition, and the development of microbiota-based therapies. By bridging these gaps, this review seeks to provide a comprehensive understanding of the mechanistic role of microbiota immune tolerance and its potential as a novel therapeutic target for autoimmune and inflammatory diseases.
    Keywords:  Treg; gut microbiota; immune modulation; immune tolerance; probiotics
    DOI:  https://doi.org/10.3389/fimmu.2025.1607388
  33. Nat Commun. 2025 Oct 08. 16(1): 8809
    Selective HLA knockdown and PD-L1 expression prevent allogeneic CAR-NK cell rejection and enhance safety and anti-tumor responses in xenograft mice.
    Fuguo Liu, Mubin Tarannum, Yingjie Zhao, Yiming J Zhang, James Dongjoo Ham, Kewen Lei, Yuhao Qiang, Xingyu Deng, Maily Nguyen, Khanhlinh Dinh, Shaobo Yang, Alaa Kassim Ali, Toni K Choueiri, Jerome Ritz, Rizwan Romee, Jianzhu Chen.
      Allogeneic cellular immunotherapy exhibits promising efficacy for cancer treatment, but donor cell rejection remains a major barrier. Here, we systematically evaluate human leukocyte antigens (HLA) and immune checkpoints PD-L1, HLA-E, and CD47 in the rejection of allogeneic NK cells and identify CD8+ T cells as the dominant cell type mediating allorejection. We demonstrate that a single gene construct that combines an shRNA that selectively interferes with HLA class I but not HLA-E expression, a chimeric antigen receptor (CAR), and PD-L1 or single-chain HLA-E (SCE) enables the one-step construction of allogeneic CAR-NK cells that evade host-mediated rejection both in vitro and in a xenograft mouse model. Furthermore, CAR-NK cells overexpressing PD-L1 or SCE effectively kill tumor cells through the upregulation of cytotoxic genes and reduced exhaustion and exhibit a favorable safety profile due to the decreased production of inflammatory cytokines involved in cytokine release syndrome. Thus, our approach represents a promising strategy in enabling "off-the-shelf" allogeneic cellular immunotherapies.
    DOI:  https://doi.org/10.1038/s41467-025-63863-8
  34. Cureus. 2025 Sep;17(9): e91592
    Pediatric Applications of Digital Therapeutics: Clinical Evidence and Implementation Landscape.
    Venkata Sushma Chamarthi.
      Digital therapeutics (DTx) are evidence-based software interventions designed to prevent, manage, or treat medical conditions through validated therapeutic mechanisms of action. They are emerging as a transformative paradigm in pediatric healthcare, where accessibility, engagement, and personalization are particularly critical. This review examines the landscape of prescription digital therapeutics for children and adolescents, focusing on current applications, regulatory considerations, implementation challenges, and future innovations. Although only a limited number of prescription digital therapeutics have been formally authorized for pediatric use, early examples demonstrate feasibility and therapeutic benefit for conditions such as attention-deficit/hyperactivity disorder (ADHD) and amblyopia. Beyond these, research is rapidly expanding into a broader set of conditions, including autism spectrum disorders, anxiety, substance use prevention, and management of chronic illnesses, highlighting the potential of digital therapeutics to complement traditional treatment approaches in specific contexts. Despite this promise, several barriers to implementation remain, with access constrained by the digital divide, socioeconomic disparities, and variability in insurance reimbursement. Additional challenges include ensuring developmental appropriateness, addressing privacy and safety concerns specific to children, and creating sustainable clinical integration pathways. Looking ahead, emerging technologies such as artificial intelligence-driven personalization, immersive virtual and augmented reality environments, and integration with wearable devices offer opportunities to overcome current limitations. Pediatric digital therapeutics hold promise as tools that may advance precision medicine, though current evidence is limited mainly to a few conditions, such as ADHD and amblyopia. With the potential to deliver scalable, cost-effective, and engaging interventions that expand access to high-quality care for children worldwide.
    Keywords:  amblyopia; attention-deficit/hyperactivity disorder (adhd); digital therapeutics; pediatrics; virtual reality
    DOI:  https://doi.org/10.7759/cureus.91592
  35. Neurol Neuroimmunol Neuroinflamm. 2025 Nov;12(6): e200479
    Anti-CD19 CAR T-Cell Therapy in Advanced Stiff-Person Syndrome and Concomitant Myasthenia Gravis.
    Ilya Ayzenberg, Athina-Maria Aloizou, Clarissa Lohmann, Simon Faissner, Christiane Schneider-Gold, Dominic Borie, Thomas Mika, Roland Schroers, Jeremias Motte, Ralf Gold.
       BACKGROUND: Autologous chimeric antigen receptor (CAR) T-cell therapy has recently gained interest in the treatment of rheumatic and neuroimmunologic diseases.
    METHODS: We report a 62-year-old female patient with a 14-year history of treatment-refractory anti-GAD-positive stiff-person syndrome (SPS) and concomitant anti-AChR-positive myasthenia gravis. Despite a relatively stable disease course in the first 8 years, SPS dramatically progressed afterward. In 2023, she was able to walk less than 10-15 m and suffered from severe persistent stiffness in the left arm superimposed with painful muscle spasm attacks (MSAs). Numerous immunotherapies, including intravenous immunoglobulins, plasma exchange, steroids, azathioprine, and rituximab, were ineffective. Consequently, she was escalated to compassionate use of autologous anti-CD19 CAR T-cell therapy (KYV-101).
    RESULTS: From the third month post-CAR-T, we observed a substantial improvement in walking distance, pain, anxiety, and MSAs in the arm. By the sixth month, she was able to walk 500 m. The anti-GAD titers declined from 1:320 to 1:32. Side effects included grade 2 cytokine release syndrome and moderate leukopenia, without serious infections.
    DISCUSSION: CAR T-cell therapy was effective at mitigating SPS symptoms, despite the long history and severe refractory disease course in our patient. Controlled trials are needed to evaluate its potential in SPS.
    DOI:  https://doi.org/10.1212/NXI.0000000000200479
  36. Expert Opin Pharmacother. 2025 Oct 08. 1-11
    A review of safe and effective pharmacotherapies for Pediatric and neonatal septic shock.
    Mahima Chandrasekhar, Simon Nadel.
       INTRODUCTION: Sepsis is a clinical syndrome that occurs due to dysregulated host response to infection. Septic shock is the presence of cardiovascular dysfunction in the context of sepsis. Pediatric septic shock is an important cause of morbidity and mortality globally. Early recognition and prompt treatment has been shown to improve outcomes.
    AREAS COVERED: A comprehensive literature search was conducted using PubMed and Embase. Key search terms included 'Paediatric,' sepsis,' 'shock,' 'neonatal,' 'antimicrobial,' and 'adjunctive therapy' from 1965 to date.
    EXPERT OPINION: The primary focus underlying management of neonatal and pediatric septic shock is rapid recognition and timely antibiotic and fluid therapy, with initiation of supportive treatments. Disappointingly, this management paradigm has not significantly changed in the last 20 years, despite efforts to develop novel adjunctive therapies.What has changed is the recognition that 'bundles of care' including rapid diagnosis, appropriate antibiotics, fluid resuscitation, and initiation of supportive care can significantly improve outcomes.Molecular diagnostics have significantly improved the ability for effective antimicrobial stewardship. Initiatives such as the Surviving Sepsis Campaign have highlighted evidence-based practice. However, few new adjunctive therapies have been translated from research into clinical practice, but there are several potential advances in treatment modalities that will be discussed.
    Keywords:  Pediatric; guidelines; sepsis; shock; therapies
    DOI:  https://doi.org/10.1080/14656566.2025.2571144
  37. Drug Dev Res. 2025 Nov;86(7): e70167
    Targeting mTOR Kinase for Cancer Treatment: A Comprehensive Review With Clinical Insights.
    Md Takdir Hossain, Md Arafat Hossain.
      Cancer remains a significant global health challenge, with increasing incidence and mortality rates worldwide. The mechanistic target of rapamycin (mTOR) pathway, a central regulator of cell growth, proliferation, metabolism, and survival, has emerged as a promising therapeutic target in cancer. Dysregulation of mTOR signaling is implicated in various cancers, including breast, colon, lung, renal cell carcinoma, and multiple myeloma, making it an attractive target for inhibition. This review provides a comprehensive analysis of mTOR-targeted therapies, focusing on the clinical outcomes, efficacy, safety, and adverse effects of mTOR inhibitors. We explore the mechanisms of mTOR regulation, the impact of mTOR mutations on drug sensitivity, and the development of resistance to mTOR inhibitors. The review also highlights the potential of combination therapies and next-generation inhibitors to overcome resistance and improve therapeutic outcomes. Key mTOR inhibitors, including rapalogs (e.g., sirolimus, everolimus) and ATP-competitive inhibitors (e.g., MLN0128, PP242), are discussed in detail, along with their clinical applications and limitations. Additionally, we summarize the findings from major clinical trials, including FDA-approved mTOR inhibitors like everolimus and temsirolimus, and non-FDA-approved inhibitors such as sapanisertib and ridaforolimus. The review underscores the importance of understanding mTOR signaling and its role in cancer progression, offering insights into the future of mTOR-targeted therapies in oncology.
    Keywords:  clinical trials; mTOR inhibitors; mTOR signaling pathway; targeted therapy; therapeutic resistance
    DOI:  https://doi.org/10.1002/ddr.70167
  38. Nat Rev Cancer. 2025 Oct 10.
    Decoding ferroptosis for cancer therapy.
    Adam Wahida, Marcus Conrad.
      Resisting cell death is a pivotal hallmark of cancer and one of several increasingly actionable functional capabilities acquired by cancer cells to sustain their malignant state. Since the early 2000s, the discovery of multiple regulated cell death programmes has intensified interest in targeting these maladaptive traits that cancer cells employ to resist cellular demise. Among these, ferroptosis - the lethal outcome of iron-dependent (phospho)lipid peroxidation - stands apart from other regulated cell death mechanisms, as it is persistently suppressed while lacking an activating signal. In cancer research, ferroptosis has garnered considerable attention, with growing evidence suggesting that its deregulation intersects with other hallmarks of malignancy, thus positioning it as a pleiotropic target. However, in the absence of approved ferroptosis-based drugs and despite substantial advances in understanding the metabolic manoeuvres of cancer cells to evade ferroptosis, its heralded translational value remains somewhat speculative at this stage. This Review reconciles the biochemical foundation of ferroptosis, the evidence supporting its role in cancer biology and the potential strategies for rationalizing targeted therapies to induce ferroptosis-prone states in malignancies. Building on this foundation, we explore contentious issues surrounding ferroptosis, including its implications for immunogenicity and redox imbalances in cancer. Finally, we address critical considerations such as therapeutic windows and biomarkers of ferroptosis, which are prerequisites for successful translation into clinical oncology.
    DOI:  https://doi.org/10.1038/s41568-025-00864-1
  39. Brain. 2025 Oct 06. pii: awaf373. [Epub ahead of print]
    Ageing and remyelination failure in people with multiple sclerosis.
    Trisha Mukherjee, Christopher E McMurran, Jonathon Holland, Cyrus Daruwalla, Gioia Riboni-Verri, J William L Brown, Robin J M Franklin, Alasdair Coles, Nick G Cunniffe.
      One of the most promising strategies to delay, prevent, or reverse disability progression in multiple sclerosis (MS) is enhancing endogenous remyelination. While preclinical research has established a strong connection between ageing and remyelination failure, evidence for this same link in people with MS remains less secure. As clinical trials for remyelinating therapies progress, clarifying this relationship is essential. A deeper understanding could guide the selection of therapeutic candidates, refine patient selection, and optimise the timing of treatment delivery. In this review, we describe the available evidence that has investigated the impact of age on remyelination in people with MS. We categorise these into pathological, imaging and clinical studies. We explore the challenges in measuring remyelination in humans and determine the implications for the connection between remyelination and age. Current evidence suggests that there is reduced capacity for remyelination with advancing age in people with MS. However, these findings are at times inconsistent and the precise contribution of ageing to remyelination failure is unclear. There does not appear to be an age cut-off beyond which remyelination is not possible, as there are pathological data supporting remyelination occurring, to some extent, across all ages. Interestingly, the impact of age may vary by lesion location. Further targeted research, specifically exploring the relationship between ageing and remyelination, is needed. With emerging evidence that ageing processes might be malleable, we conclude that targeting the biology of ageing might also be an important strategy to therapeutically enhance remyelination.
    Keywords:  biological ageing; g-ratio; magnetization transfer ratio; myelin; oligodendrocyte precursor cell; visual evoked potentials
    DOI:  https://doi.org/10.1093/brain/awaf373
  40. PLoS One. 2025 ;20(10): e0332736
    Immune repertoire profiling and T cell dysregulation in Peripheral Blood Mononuclear Cells of Type 2 diabetic patients.
    Zheng Bi, Fanjing Wang, Shengmao Wang, Zhaohui Fang.
       OBJECTIVE: The prevalence of diabetes mellitus (DM) is escalating globally, presenting a significant public health challenge. The immune system, particularly T cells, plays a crucial role in the pathogenesis of diabetes. This study aims to elucidate the characteristics of T cell receptors (TCRs) and immune dysregulation within peripheral blood mononuclear cells (PBMCs) of diabetic patients, with exploratory analysis of microbial profiles.
    METHODS: We employed high-throughput RNA-seq to analyze the protein-coding genes expression, and function enrichment with different expression, BCR/TCR repertoires and microbial communities in PBMC samples collected from both diabetic patients and healthy controls. Comparative analysis was conducted to identify distinct TCR signatures associated with diabetes. Microbial communities were secondarily assessed via unmapped RNA-seq reads.
    RESULTS: Overall, we found different patterns of gene expression, gene function, immune cell proportion, immune repertoire and microbiome between the different DM and control groups. 1145 upregulated 400 down-regulated genes were identified, and immune response function terms were enriched, such as, cell-cell adhesion via plasma-membrane adhesion molecules, and homophilic cell adhesion via plasma membrane adhesion molecules (BP); as well as in the T cell receptor complex, plasma membrane signaling receptor complex, alpha-beta T cell receptor complex (CC), and in antigen binding and immunoglobulin receptor binding (MF). Furthermore, reactome pathway enrichment analysis revealed enrichment of these DEGs in Viral mRNA Translation, Influenza Viral RNA Transcription and Replication, SARS-CoV-1 modulates host translation machinery, Interleukin-6 family signaling, etc. DM PBMC showed significantly lower chao1 index of TCR (including TCRA and TCRB) and reduced expression of TRAV/TRBV genes compared to controls. Enriched pathways included T cell receptor complex, antigen binding, and interleukin-6 signaling. Exploratory analysis of microbial reads revealed decreased alpha diversity (chao1/ACE) in DM and 123 altered taxa, though microbial abundance was low.
    CONCLUSION: Our study provides novel insights into T cell receptor dysregulation in diabetes. The role of PBMC-associated microbiota requires further validation.
    DOI:  https://doi.org/10.1371/journal.pone.0332736
  41. J Immunother Cancer. 2025 Oct 10. pii: e011709. [Epub ahead of print]13(10):
    Claudin 6 is a suitable target for CAR T-cell therapy in atypical teratoid/rhabdoid brain tumors and other pediatric solid tumors.
    Peter J Madsen, Anna Melissa Schlitter, Carina Flemmig, Conor Dickson, Kyra Harvey, Cullen Wilson, Ezra Beaubien, Luke Patterson, Allison Stern, Crystal Griffin, Nikhil Joshi, Sreehita Hajeebu, Daniel Martinez, Phillip B Storm, Adam C Resnick, Peter Hillemanns, Martin Stanulla, Jörg Faber, Arthur Wingerter, Matthias Martin Gaida, Saskia Holtemeyer, Mark Laible, Anja Feldner, Florian Frohns, João H Duarte, Bruno Valentin Sinn, Stefan Wöll, Ugur Sahin, Özlem Türeci, Jessica B Foster.
       BACKGROUND: Solid tumors comprise approximately 60% of all pediatric cancers. Relapsed or refractory tumors of the central nervous system (CNS), such as atypical teratoid/rhabdoid tumors (AT/RTs), are the leading cause of death in children with cancer. Claudin 6 (CLDN6)-specific chimeric antigen receptor (CAR) T cells have demonstrated activity in preclinical and clinical studies in various solid adult cancers. However, the suitability of CLDN6 as a target in pediatric tumors and their susceptibility to CAR T-cell therapy has yet to be established. This study aimed to evaluate the suitability of CLDN6 as a target for CAR T-cell therapy of pediatric solid tumors.
    METHODS: Immunohistochemical CLDN6 expression was assessed in fetal normal tissues (n=91), pediatric normal tissues (n=157), and two sets of pediatric tumor tissues (n=527 and n=49) using a combined score that includes the percentage of stained cells with a 4-point intensity scale (0 to 3+). The antitumor activity of CLDN6 RNA-transduced CAR T cells against AT/RT cell lines was assessed with in vitro assays and in immunodeficient NOD-SCID-γc-/- (NSG) mouse models bearing orthotopic xenograft tumors.
    RESULTS: Membranous CLDN6 expression, as detected by immunohistochemistry, was widely observed in fetal tissues but was absent in almost all non-malignant pediatric tissues, except for very rare, scattered cells with 1+ to 2+ intensity in kidney, pancreas, pituitary, and salivary gland tissues. Membranous CLDN6 expression was frequently detected in a subset of the pediatric tumor entities, including germ cell tumors (93% of samples with CLDN6-positive cells), nephroblastoma (64%), extracranial malignant rhabdoid tumors (50%), and AT/RTs (39%). In CLDN6-positive samples, CLDN6 was generally expressed with 2+ or 3+ intensity in substantial proportions of the cancer cells. Strong CLDN6 expression was also detected in single samples of hepatoblastoma, Ewing sarcoma/other embryonal tumors, and osteosarcoma.In experimental models, CLDN6-CAR T cells led to antigen-specific killing of endogenously CLDN6-expressing AT/RT cell lines in vitro and exhibited potent and specific antitumor activity in mice bearing orthotopic CLDN6-expressing AT/RT xenograft tumors.
    CONCLUSIONS: These results support CLDN6 as an oncofetal cell-surface antigen that may be suitable for CAR T-cell targeting in pediatric solid tumors, including those of the CNS.
    Keywords:  Biomarker; Central Nervous System Cancer; Chimeric antigen receptor - CAR; Solid tumor
    DOI:  https://doi.org/10.1136/jitc-2025-011709
  42. Adv Immunol. 2025 ;pii: S0065-2776(25)00006-9. [Epub ahead of print]167 123-173
    Modulation of humoral immunity by γδ T cells: A potential adjuvant strategy for vaccination.
    Kirsty Emery, Matthias Eberl.
      Vaccination is arguably the most effective intervention in reducing the impact of infectious diseases. However, many vaccines provide only partial or transient protection, prompting the need for more effective solutions based on our growing understanding of the pivotal role of CD4+ T follicular helper (Tfh) cells in humoral immunity and how they interact with B cells. Here we review how γδ T cells can boost antibody responses via crosstalk with both Tfh and B cells, which could lead to new adjuvant strategies to improve vaccination efficacy, achieve long-lasting protective immunity and prevent major infectious diseases of global importance.
    Keywords:  Adjuvant; B cells; Broadly neutralising antibodies; HIV; Humoral immunity; Malaria; T follicular helper cells; Tuberculosis; Vaccines; γδ T cells
    DOI:  https://doi.org/10.1016/bs.ai.2025.05.001
  43. Nanoscale. 2025 Oct 07.
    Nanozyme-driven remodeling of the immune microenvironment: from catalytic therapy to precise immune regulation.
    Qian He, Liyun Zhang.
      Nanozymes have emerged as transformative tools for addressing critical challenges in diseases characterized by immune dysregulation, including cancer, chronic inflammation, and persistent infections. These enzyme-mimicking nanomaterials offer unique advantages in remodeling pathological immune microenvironments through their tunable catalytic activities and precise spatiotemporal control. This review systematically examines recent breakthroughs in nanozyme-based immunomodulation, highlighting their ability to induce immunogenic cell death and activate innate immune pathways in cancer therapy, simultaneously scavenge reactive species and reprogram macrophage polarization in inflammatory diseases, and disrupt microbial biofilms while resolving infection-associated immunosuppression. We critically analyze key innovations in single-atom catalysts, bioinspired delivery systems, and novel catalytic-immune mechanisms that enable targeted immune regulation. By elucidating fundamental structure-activity relationships and translational challenges, this review provides valuable insights for developing next-generation nanozyme immunotherapies with enhanced specificity and clinical potential. These advances establish nanozymes as powerful platforms for precision immunotherapy across a broad spectrum of immune-related disorders.
    DOI:  https://doi.org/10.1039/d5nr03420e
  44. Biogerontology. 2025 Oct 10. 26(5): 190
    Therapeutic extracellular vesicles as a cornerstone of medicine in the next decade with gerontological focus.
    Alexander Yu Pulver, Roman E Tokmachev, Natalie A Pulver, Lyubov N Antakova, Mariia A Emelianova.
      Extracellular vesicles present a promising alternative to stem cells in regenerative medicine and gerontology. They offer significant advantages over cell transplantation, demonstrating potential for slowing aging and treating age-related diseases. Extracellular vesicles secreted by diverse cell types modulate inflammation, stimulate tissue regeneration, and exhibit anti-inflammatory and immunomodulatory properties. This work explores the therapeutic potential of extracellular vesicles as alternatives to cell therapy, examining their key advantages and current limitations. It specifically focuses on their roles within established aging mechanisms and their dual utility as biomarkers and therapeutic agents. Critical aspects of extracellular vesicle translation are addressed, including standardized methods for production, storage stability optimization, and engineering strategies for cargo loading and targeting. Extracellular vesicles possess unique biological properties-inherent biocompatibility, low immunogenicity, ability to cross biological barriers, and high biological activity at low doses. Preclinical studies across various age-related pathologies (neurodegeneration, cardiovascular disease, sarcopenia) consistently report efficacy in reducing inflammation, promoting tissue repair, and improving functional outcomes. These findings strongly support the capacity of extracellular vesicles to mimic many therapeutic effects of parental cells while mitigating risks like tumorigenicity or immunorejection associated with whole-cell therapies. Overcoming challenges in scalable manufacturing, quality control, regulatory standardization, and targeted delivery is essential for the clinical translation of extracellular vesicles. Despite these hurdles, their compelling preclinical evidence and inherent advantages position them as a major future direction. They are expected to play a key role in combating age-related decline and advancing regenerative medicine, becoming a cornerstone of next-generation biomedical interventions over the next decade.
    Keywords:  Extracellular vesicles; Gerontology; Heterochronic parabiosis; Plasmapheresis; Regenerative medicine; Rejuvenation
    DOI:  https://doi.org/10.1007/s10522-025-10332-w
  45. Microb Physiol. 2025 Oct 03.
    Microbiome: Friend or Friendly Foe.
    Lakshmi B Reddy, Milton H Saier.
      The human microbiome is a dynamic, polymicrobial ecosystem that plays an essential role in nutrition, immune development, barrier integrity, and host physiology, acting as a mutualistic partner under balanced conditions. However, its ecological complexity, genetic adaptability through horizontal gene transfer, and interactions with other prokaryotes as well as protozoan and metazoan parasites can transform commensals into pathobionts, resulting in weakened host's barriers, immunity declines with the progression of age, and community composition shifts toward dysbiosis. Factors such as diet, genetics, aging, immune-senescence, impaired autophagy, and environmental exposure, all influence this delicate balance, determining whether the microbiome remains protective or becomes an opportunistic source of inflammation and disease. This review focuses on the study of the intestinal microbiome in humans. Maintaining microbiome homeostasis is promoted through (a) dietary diversity, (b) limited antimicrobial use, (c) use of probiotics, (d) support for gut barrier function, and (e) healthy lifestyle improvements. These actions and considerations are critical to prevent the emergence of pathogenic states and preserving the microbiome's vital role in host health throughout life.
    DOI:  https://doi.org/10.1159/000548748
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