bims-carter Biomed News
on CAR-T Therapies
Issue of 2026–03–01
fifty-two papers selected by
Luca Bolliger, lxBio
  1. Commentary on "Comparative efficacy and safety of PSCA CAR-engineered Vδ1 γδ T cells for immunotherapy of pancreatic cancer".
  2. CAR T cells and T cell engagers for autoimmunity-lessons from hematology.
  3. Self-amplifying RNA-based CAR T cell therapy with enhanced duration and multi-genic logic function.
  4. CERTOMICS: Trusted Single-Cell Multiomics Pipeline for High-Resolution Profiling of Adoptive Cellular Immunotherapies.
  5. Overcoming functional and translational challenges of cellular immunotherapies for solid tumors.
  6. In Vivo CAR-T Therapies-A New Era of Programmable Immunity.
  7. Epigenetic editing to advance CAR T cell therapy.
  8. CAR-T Cell Therapy in Glioblastoma: Overcoming Immunological Barriers and Advancing Clinical Translation.
  9. Cardiotoxicity of T cell immunotherapies.
  10. γδ T Cells for Cancer Immunotherapy: Unconventional Players Take the Spotlight.
  11. Nanomedicine Meets Immunotherapy: Transforming Chimeric Antigen Receptor T Cell Treatment for Solid Tumors.
  12. Advancing real-world evidence harmonization: lessons from the UK, EMA and global policy frameworks.
  13. T cell-inspired therapeutic delivery platforms: From nanomedicines to cell therapy.
  14. Roles of the gut microbiota in cancer immunotherapy: Mechanistic foundations and therapeutic opportunities.
  15. Immune cell separation for cell therapy: A comprehensive review of techniques, and challenges.
  16. Ready or Not, Here They Come: A Practical Guide to Adoptive T cell Therapies for Solid Tumors for Medical Oncologists.
  17. Stem Cell-Based Therapies in Autoimmune Diseases: Current Evidence, Unmet Needs, and Future Directions-A Closing Editorial Review.
  18. CAR T-Cell Immunotherapy in Neuroautoimmune Diseases: Focus on the Central Nervous System.
  19. Advances in T cell-based immunotherapy for osteosarcoma.
  20. Enhancing Patient-Centered Health Technology Assessment: A Modified Delphi Panel for PICOS Scoping in Spinal Muscular Atrophy.
  21. CD19 exon 2 skipping is a potential prognostic correlate of anti-CD19 CAR-T therapy relapse.
  22. How can we balance risk and benefit of interleukin-18 armored T cell therapies?
  23. Next-generation CAR-T and CAR-NK cell therapies in hematologic malignancies: engineering for persistence, specificity, and safety.
  24. Human serum influences functional plasticity and transcriptomic landscape of γδ T cells in vitro.
  25. A novel GMP-manufactured medicinal product candidate composed of NK and γδ T cells as adjunct immunotherapy for hematopoietic stem cell transplantation.
  26. Applications of AI & ML in Biomanufacturing of Cell and Gene Therapies.
  27. Global Panoramic analysis of clinical research in cell therapy: clinical trial landscape, marketed products, and regulatory trends.
  28. Thermal sonogenetics for adoptive cell transfer therapy.
  29. Health technology assessment and medical insurance access for rare disease drugs in China: A policy review with quantitative insights from publicly available data.
  30. Cord blood in a rapidly evolving biotherapies landscape.
  31. Development of tri-cistronic CLDN18.2 CAR-T cells incorporating PD-1/CD28 switch and cyclophilin A for enhanced solid tumor immunotherapy.
  32. Engineering Kidney-Targeted Drug Delivery Systems: Principles, Materials, and Emerging Strategies.
  33. PhIP-Seq: unveiling the complexity of antibody repertoires in health and disease.
  34. Advances in Next-Generation Immunotherapies for Ovarian Cancer: Mechanisms of Immune Evasion and Novel Therapeutic Targets.
  35. Pulmonary Drug Delivery for Infectious Diseases: Cutting-Edge Formulations and Manufacturing Technologies.
  36. Re-imagining T-cell receptor signaling: parallel paths may be key to discriminatory power.
  37. Drug Product Development of Lipid Nanoparticle-Based mRNA Therapeutics and Vaccines.
  38. Personalizing Nutritional Therapy in Pediatric Oncology: The Role of Gut Microbiome Profiling and Metabolomics in Mitigating Mucositis and Enhancing Immune Response to Chemotherapy.
  39. Progress in sepsis prediction models: from traditional scoring systems to multimodal intelligence and clinical translation.
  40. From Promise to Practice: Harmonizing Telemedicine in Pediatric Chronic Respiratory Diseases.
  41. Global trends of peripheral immune tolerance research: a bibliometric and visualization analysis.
  42. Determinants of Efficacy and Optimization of Chimeric Antigen Receptor T-Cell Therapy for Treating Multiple Myeloma: Current Status and Future Perspectives.
  43. Red Blood Cell-Derived Extracellular Vesicles for Gene and RNA Therapeutics: Biological, Engineering, and Translational Challenges.
  44. Nursing Informatics and Undergraduate Nursing Curricula: A Scoping Review.
  45. The Need for Clinical Trial Dataset Specifications to Support Clinical Pharmacology Review of Immunogenicity.
  46. Recent Advances in Nanoparticle-Based Drug Delivery Strategies to Cross the Blood-Brain Barrier in Targeted Treatment of Alzheimer's Disease.
  47. Goodbye P<0.05. P-value is simply one item among many to gauge scientific evidence.
  48. The fetal frontier: A review of current and emerging fetal therapies for genetic diseases.
  49. In vivo CAR-T engineering: insights from the 2025 ASH annual meeting.
  50. Epigenetic modulation to overcome immune suppression in pancreatic cancer.
  51. Innovative approaches targeting innate immune cells to promote organ transplant tolerance.
  52. Targeting immune checkpoint therapy: The role of manganese in tumor immunotherapy.
  1. J Immunother Cancer. 2026 Feb 24. pii: e014199. [Epub ahead of print]14(2):
    Commentary on "Comparative efficacy and safety of PSCA CAR-engineered Vδ1 γδ T cells for immunotherapy of pancreatic cancer".
    Dorine A de Bont, Trudy Straetemans, Zsolt Sebestyén, Jurgen Kuball.
      Adoptive transfer of unmodified γδ T cells has shown limited clinical benefit, prompting a shift toward chimeric antigen receptor (CAR) engineering to enhance activation, persistence, and tumor specificity. CAR technology positions γδ T cells as promising carriers due to their innate-like cytotoxicity and HLA-independent recognition. Evidence from αβ CAR T-cell trials indicates that γδ CAR T cells can persist for months to years post-infusion, suggesting their potential contribution to long-term immune surveillance against cancer. Among γδ subsets, Vγ9Vδ2 T cells dominate peripheral blood and have been preferentially used for CAR engineering. Recent advances, however, enable the expansion of Vδ1 T cells, known for their tissue residency and resistance to exhaustion. In a key comparative study, Li et al benchmarked PSCA-targeted CARs in Vδ1, Vγ9Vδ2, and αβ T cells, showing similar short-term tumor control but distinct transcriptional and phenotypic programs. These findings highlight the need for subset-specific optimization of γδ CAR-T therapies. Early studies in hematologic malignancies could provide a practical proof of concept, before tackling the additional challenges of solid tumors. Such focused development may be essential to advance the γδ CAR-T field amid tightening industry investment.
    Keywords:  Adoptive cell therapy - ACT; Hematologic Malignancies; Immunotherapy; Solid tumor; T cell
    DOI:  https://doi.org/10.1136/jitc-2025-014199
  2. Bone Marrow Transplant. 2026 Feb 23.
    CAR T cells and T cell engagers for autoimmunity-lessons from hematology.
    Sarah Kayser, Arnon Nagler.
      Autoimmune diseases are driven by dysregulated immune responses against self-antigens, resulting in chronic inflammation and progressive tissue damage. Chimeric antigen receptor (CAR) T cell therapy and T cell engagers, initially developed for the treatment of hematologic malignancies, have demonstrated that they can mediate profound and sustained depletion of pathogenic B cells, leading to long-term remissions in otherwise refractory diseases. In this review, we explore key insights gained from hematologic applications of CAR T cells and T cell engagers, and discuss how these lessons can guide the clinical use of these therapies in autoimmune diseases.
    DOI:  https://doi.org/10.1038/s41409-026-02808-1
  3. bioRxiv. 2026 Feb 20. pii: 2026.02.18.706661. [Epub ahead of print]
    Self-amplifying RNA-based CAR T cell therapy with enhanced duration and multi-genic logic function.
    Yuyang Gu, Jaehoon Choi, Devin Mutha, Christopher Wu, Neil J Ganem, Mark W Grinstaff, Wilson W Wong.
      Chimeric antigen receptor T (CAR-T) cell therapy is transforming the treatment landscape of hematological malignancies. However, manufacturing with integrating viral vectors is costly, slow, and carries risks including insertional mutagenesis, prolonged B cell aplasia, and other long-term toxicities. Expression of CAR with mRNA can reduce cost, manufacturing timelines, and improve safety. However, the short-lived expression necessitates frequent repeat dosing. Here, we describe a modified self-amplifying RNA (saRNA) platform for engineering CAR T cells with prolonged CAR expression and enhanced durability of tumor control relative to mRNA CAR T cells. In an acute lymphoblastic leukemia (ALL) xenograft model, saRNA CAR T cells achieve superior tumor suppression and prolong survival. Further, a single-strand modified saRNA supports the co-expression of multiple proteins, enabling the construction of advanced CAR systems, such as OR- and AND-gated logic CAR T cells. Together, these results highlight saRNA as a powerful and versatile platform for CAR T cell engineering with favorable safety, efficacy, and accessibility.
    DOI:  https://doi.org/10.64898/2026.02.18.706661
  4. Bioinformatics. 2026 Feb 25. pii: btag096. [Epub ahead of print]
    CERTOMICS: Trusted Single-Cell Multiomics Pipeline for High-Resolution Profiling of Adoptive Cellular Immunotherapies.
    Christina Katharina Kuhn, David Schmidt, Michael Rade, Josephine Selke, U Sandy Tretbar, Maximilian Merz, Jan Grau, Kristin Reiche.
       SUMMARY: Adoptive cellular immunontherapies, such as chimeric antigen receptor (CAR) T cell therapy, have transformed cancer treatment, yet challenges such as resistance, relapse, and high costs limit their efficacy and accessibility. A comprehensive understanding of cellular heterogeneity and molecular profiles is essential to improve these therapies. Advanced single-cell multiomics technologies have the power to analyze the complex interactions between CAR-engineered cells, immune cells, and tumor cells. However, standardized single-cell multiomics computational pipelines specifically tailored to CAR-engineered cell products are lacking. Due to the synthetic nature of CAR transgenes, additional steps for reliable identification and characterization of CAR-positive cells are required but not included in existing data-processing workflows. To address this, we present CERTOMICS, a Nextflow-based, CAR-aware pipeline offering enhanced CERTainty in immunophenotyping and data interpretation, tailored for single-cell multiOMICSprofiling of adoptive cellular immunotherapies. The pipeline standardizes processing 10x Genomics single-cell multiomics data and integrates CAR-specific identification and quality control. Additionally, a curated repository of CAR construct sequences and annotation data is provided, serving as an extensible resource to support the analysis and development of CAR T cell therapies.
    AVAILABILITY AND IMPLEMENTATION: Detailed documentation of this pipeline, along with a resource on latest FDA-approved CAR therapies is available on our website: https://fraunhofer-izi.github.io/Living-Drugs-Wiki/. The source code can be viewed at https://github.com/fraunhofer-izi/CERTOMICS. The code is also published on Zenodo at https://doi.org/10.5281/zenodo.18709693.
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    Keywords:  Adoptive Cellular Immunotherapy; CAR T cell therapy; Chimeric Antigen Receptor; Single-cell multiomics
    DOI:  https://doi.org/10.1093/bioinformatics/btag096
  5. Cancer Cell. 2026 Feb 26. pii: S1535-6108(26)00101-7. [Epub ahead of print]
    Overcoming functional and translational challenges of cellular immunotherapies for solid tumors.
    Yi-Ching Chen, Kok-Siong Chen, Bruce L Levine, Khalid Shah.
      In recent years, immunotherapy has revolutionized the landscape of cancer treatment, offering promising avenues for patients with otherwise limited outcomes. Among the most promising modalities are cell-based therapies, including autologous and allogeneic approaches such as engineered T cells, NK cells, stem cells and cell-based vaccines. These therapies harness the inherent capabilities of immune cells to recognize and eliminate cancer cells. Although cell therapies have shown remarkable clinical efficacy in hematologic malignancies, critical hurdles impede their efficacy for the treatment of solid tumors. This review examines the key challenges that hinder the broader clinical-translation of autologous and allogeneic cell-based cancer therapies in treating solid tumors. These include functional challenges that limit therapeutic efficacy and translational challenges that impede the clinical development and implementation of promising cellular therapies. We highlight contributing factors and evaluate potential solutions, emphasizing the synergistic potential of innovative engineering strategies, combination approaches, and emerging technologies to forge the next generation of cellular immunotherapies for solid tumors.
    Keywords:  Cancer; Cellular therapy; Functional and Translational Challenges; Solid Tumors; immunotherapy
    DOI:  https://doi.org/10.1016/j.ccell.2026.02.002
  6. Int J Mol Sci. 2026 Feb 11. pii: 1737. [Epub ahead of print]27(4):
    In Vivo CAR-T Therapies-A New Era of Programmable Immunity.
    Stefano Pierini, Rehman Qureshi, Sergei Pustylnikov, Zhanna Bartosh, Tatiana Akimova.
      Ex vivo chimeric antigen receptor (CAR) T cell therapies have achieved remarkable clinical success over the past decade, enabling effective treatment of several hematologic malignancies once considered incurable. However, their broader use remains limited. Barriers include complex and costly manufacturing, long production timelines, and risk of significant side effects and toxicities, challenges that have been further exacerbated by the reduced investment across the biotech sector since 2022. Emerging in vivo CAR-T approaches seek to overcome many of these limitations by generating CAR-T cells directly within the patient, most commonly using lentiviral or lipid nanoparticles (LNPs) delivery vectors. This strategy has the potential to streamline production, allow more tunable and repeatable dosing, and markedly reduce overall costs. However, it also raises new questions regarding genomic safety, the specificity and durability of CAR expression, host immune responses, pharmacokinetics, and regulatory oversight. In this review, we summarize the major and emerging in vivo CAR-T delivery platforms-analyzing their underlying technology, preclinical and clinical performance, and developmental paths-and discuss the scientific, technical, and biological challenges shaping this rapidly emerging field. We further outline future directions and opportunities in the field of programmable T cell immunity.
    Keywords:  CAR-T; LNPs; T cell engineering; gene delivery; gene therapy; in vivo CAR-T; lipid nanoparticles; non-viral vectors
    DOI:  https://doi.org/10.3390/ijms27041737
  7. Clin Epigenetics. 2026 Feb 23.
    Epigenetic editing to advance CAR T cell therapy.
    Laura Horvathova, Marianne G Rots, Valerie R Wiersma.
      Chimeric antigen receptor (CAR) T cell therapy has revolutionized cancer treatment by enabling the selective targeting and elimination of tumor cells. Although CAR T therapy offers a potential cure for haematological cancers, 40-60% of patients do not reach a durable response. In solid tumors, limited infiltration and the immunosuppressive tumor microenvironment have so far hindered clinical translation. Central to these challenges are T cell-intrinsic programs, including differentiation into short-lived effector cells and progressive exhaustion. Epigenetic modifications regulate T cell activation, memory formation, and exhaustion, thereby critically shaping CAR T cell persistence and therapeutic efficacy. Early studies have demonstrated that disrupting or inhibiting key epigenetic regulators such as ten-eleven translocation 2 (TET2) or DNA methyltransferase 3A (DNMT3A) can bias CAR T cells toward memory-like, non-exhausted states with superior antitumor activity. Building on these findings, gene-targeted epigenetic editing has recently emerged as a next-generation approach, offering precise, durable, and reversible reprogramming of gene expression without introducing DNA breaks. Proof-of-concept studies have demonstrated targeted and durable silencing of key inhibitory receptors such as programmed cell death protein 1 (PD-1) and lymphocyte activation gene 3 (LAG-3) as a safe strategy to shape CAR T cell phenotypes. Beyond phenotype modulation, epigenetic editing also offers opportunities for off-the-shelf donor-derived CAR T cells by enabling stable silencing of immune rejection pathways, thereby addressing key barriers to their clinical application. This review highlights the pivotal role of epigenetic regulation in T cell biology and CAR T cell therapy, and explores how epigenetic drugs, genetic interventions, and emerging epigenetic editing strategies can be harnessed to generate more potent, persistent, and widely accessible CAR T cell therapies.
    Keywords:  CAR-T; CRISPR; Epigenetics; TALE; ZFP
    DOI:  https://doi.org/10.1186/s13148-026-02085-1
  8. Cancer Manag Res. 2026 ;18 580320
    CAR-T Cell Therapy in Glioblastoma: Overcoming Immunological Barriers and Advancing Clinical Translation.
    Parvin Pourmasoumi, Ali Pourmasoumi, Farshid Zamani, Abdollah Amini, Shiva Shokri.
      Chimeric antigen receptor (CAR) T-cell therapy has delivered unprecedented clinical benefit in hematological malignancies, yet its successful translation to solid tumors remains a major unmet clinical challenge. Glioblastoma (GBM), the most aggressive primary brain tumor, exemplifies the barriers confronting cellular immunotherapy, including profound intratumoral heterogeneity, antigenic escape, a highly immunosuppressive tumor microenvironment, and anatomical constraints imposed by the blood-brain barrier. Together, these features limit CAR-T cell trafficking, persistence and sustained antitumor activity in the central nervous system.In this Review, we examine recent advances in next-generation CAR-T engineering strategies aimed at overcoming these obstacles in GBM. Key developments include multi-antigen and logic-gated CAR designs to mitigate tumor immune evasion, armored CAR-T cells capable of cytokine delivery or resistance to suppressive mediators such as TGF-β, and checkpoint-resistant constructs to counteract functional exhaustion. We also highlight emerging delivery paradigms - including locoregional administration, viral vectors and nanotechnology-enabled platforms - designed to enhance blood-brain barrier penetration and intratumoral retention. Furthermore, we discuss combinatorial strategies integrating CAR-T therapy with immune checkpoint blockade, oncolytic virotherapy and other immunomodulatory interventions to remodel the hostile glioblastoma microenvironment and amplify therapeutic efficacy. Finally, we address the principal translational challenges that must be resolved for broader clinical implementation, including neurotoxicity, manufacturing scalability and the development of predictive preclinical models.Collectively, these multidisciplinary advances provide a roadmap for optimizing CAR-T cell therapy in glioblastoma and accelerating its translation toward durable clinical benefit.
    Keywords:  CAR-T cell therapy; antigen heterogeneity; blood–brain barrier; glioblastoma; immune checkpoint blockade; nanodelivery systems; translational challenges; tumor microenvironment
    DOI:  https://doi.org/10.2147/CMAR.S580320
  9. Nat Rev Cardiol. 2026 Feb 23.
    Cardiotoxicity of T cell immunotherapies.
    Michael A Raddatz, Ashley F Stein-Merlob, Syed S Mahmood, Sarju Ganatra, Daniel Addison, Tasha L Lin, Sarah M Larson, Eric H Yang.
      T cell immunotherapies offer a new approach to cancer therapy. Chimeric antigen receptor (CAR) T cell therapy is the most prolific of these treatments, leveraging genetically engineered T cells to augment the antitumour response. Bispecific antibodies, T cell receptor-engineered T cells and tumour-infiltrating lymphocytes have also emerged as novel T cell therapies with therapeutic benefit. As the variety of T cell therapies and indications for their use expand, a nuanced understanding of potential haemodynamic sequelae and cardiovascular toxicities is required. T cell activation can lead to massive cytokine release and excessive inflammation, termed cytokine release syndrome (CRS). Like other inflammatory syndromes, CRS can lead to cardiovascular complications, including arrhythmias, myocardial infarction and heart failure, with an incidence of cardiovascular events as high as 20% among patients who develop high-grade CRS. In this Review, we summarize the mechanisms, epidemiology and management of T cell therapy-associated CRS and subsequent cardiotoxicity. We also explore how an improved understanding of CAR T cell therapy, and other emerging T cell-based treatments, will inform the prevention and management of adverse cardiovascular events.
    DOI:  https://doi.org/10.1038/s41569-026-01265-z
  10. Annu Rev Immunol. 2026 Feb 27.
    γδ T Cells for Cancer Immunotherapy: Unconventional Players Take the Spotlight.
    Georgia Stevens, Rafael Blanco-Domínguez, Sofia Mensurado, Bruno Silva-Santos.
      The success of cancer immunotherapy depends on the mobilization of leukocytes with the capacity to eliminate tumor cells. γδ T cells represent a lymphocyte lineage with strong cytotoxic potential and abundant production of antitumor cytokines. Importantly, they are not restricted to MHC-mediated presentation of neoantigens and thus are highly suited to tackle major challenges in current immunotherapies. In this article, we review the main approaches to engage and expand γδ T cells endogenously (in patients) or exogenously (for adoptive cell therapy) against cancer. We discuss the dichotomy between activation and exhaustion of γδ T cells and how they may benefit from immune checkpoint blockade. Finally, we describe the biological properties of the two main subsets of human γδ T cells, Vδ1 and Vδ2 T cells, and how they are boosted, through genetic engineering, toward maximization of their performance as next-generation cancer immunotherapies.
    DOI:  https://doi.org/10.1146/annurev-immunol-083024-024653
  11. Small Sci. 2026 Feb;6(2): e202500596
    Nanomedicine Meets Immunotherapy: Transforming Chimeric Antigen Receptor T Cell Treatment for Solid Tumors.
    Stephen O'Rourke, Nuo Xu, Hongjun Wang, Hexin Chen.
      The emergence of effective immunotherapies has drastically revolutionized clinical management of many cancer types. Among them, chimeric antigen receptor (CAR)-T cell therapy (CTT), as a groundbreaking approach, has been considered as a "living drug," displaying unprecedented clinical outcomes with hematological malignancies, including B cell leukemia and lymphomas, and multiple myeloma. Despite the high remission rates and improved survival achieved with hematological cancers, the effectiveness of CTT in solid tumors remains largely unsatisfactory. The efficacy of CTT in solid tumors is significantly challenged by multiple factors, including tumor-antigen heterogeneity, limited T cell trafficking and infiltration, a highly immunosuppressive tumor microenvironment, and the risk of severe adverse effects. Accumulating evidence highlights the potential of nanotechnology to address these obstacles, paving the way for more effective CTT against solid tumors. Thus, this review explores to highlight the evolution and challenges of CTT in solid tumors, while summarizing the up-to-date advances of nanotechnology-enabled CTT with the intention towards the formulation of a more cohesive, personalized, and effective cancer therapy in the future.
    Keywords:  chimeric antigen receptor T cell therapy; nanomedicine; solid tumor; targeted delivery; tumor microenvironment
    DOI:  https://doi.org/10.1002/smsc.202500596
  12. J Comp Eff Res. 2026 Feb 27. e250183
    Advancing real-world evidence harmonization: lessons from the UK, EMA and global policy frameworks.
    Alexandros Sagkriotis.
      Aim: Real-world evidence (RWE) - defined here as clinical evidence derived from the analysis of real-world data (RWD) on patient health status and healthcare delivery - has become a cornerstone of regulatory and health technology assessment (HTA) decision making. However, despite broad consensus on its value, policy frameworks governing RWE generation and evaluation remain heterogeneous across jurisdictions. Importantly, this heterogeneity partly reflects the distinct purposes for which RWE is used, including regulatory safety assessment, effectiveness evaluation, health-economic modeling and natural-history research. These functional differences are not inherently problematic; however, fragmented operational requirements can create duplication, inefficiency and delays in patient access. Materials & methods: This study employed a narrative comparative policy review of RWE guidance issued by twelve major regulatory and HTA agencies, including the Medicines and Healthcare products Regulatory Agency (MHRA), the EMA, the US FDA and the Canadian Agency for Drugs and Technologies in Health (CADTH). Frameworks were compared across four domains: data quality, statistical methods, registry governance and transparency. Harmonization is defined as alignment across these domains sufficient to enable consistent planning, analysis and interpretation of RWE across jurisdictions, rather than uniformity of decision making. Results: The analysis identified convergence in high-level principles but persistent divergence in operational expectations. The MHRA emphasizes flexibility and scientific dialogue; the EMA prioritizes consistency and structured governance; and the FDA provides comprehensive but resource-intensive guidance, reflecting detailed documentation requirements, prespecified analytic expectations and extensive methodological review. HTA bodies apply additional evidentiary criteria related to comparative effectiveness and value, sustaining functional fragmentation even within the same healthcare systems. Conclusion: RWE fragmentation reflects both legitimate functional differences and avoidable operational misalignment. Progress toward harmonization therefore requires shared minimum standards and transparency mechanisms rather than additional guidance documents. The UK's post-Brexit autonomy positions it as a test environment for collaborative pilots with the European Medicines Agency, the International Council for Harmonization (ICH) and the International Coalition of Medicines Regulatory Authorities (ICMRA). Six strategic actions are proposed to support pragmatic alignment while preserving contextual flexibility.
    Keywords:  HTA; RWD; RWE; global alignment; health technology assessment; policy harmonization; real-world data; real-world evidence; regulatory science
    DOI:  https://doi.org/10.57264/cer-2025-0183
  13. Mater Today Bio. 2026 Apr;37 102909
    T cell-inspired therapeutic delivery platforms: From nanomedicines to cell therapy.
    Nasrullah Jan, Hassan Shah, Safiullah Khan, Naveed Ullah Khan, Yan Li, Xinwei Zhang, Guixiu Shi.
      Targeted nanodrug delivery has garnered significant interest as a carrier for drugs, genes, and vaccines. Despite their clinical potential, these nanocarriers face substantial challenges due to their exogenous nature. These challenges can be addressed by employing T cell-inspired approaches for targeted therapies. T cell-inspired approaches-including T cell membrane-coated nanoparticles, T cell-derived exosomes, T cell hitchhiking, and chimeric antigen receptor (CAR)-T cells-exhibit remarkable properties such as inherent biocompatibility and biodegradability, prolonged circulation lifespan, and the ability to traverse biological barriers. Utilizing T cells as delivery vehicles enables prolonged circulation time and targeted drug transport, along with reduced toxicity to cells and tissues. This review explores innovative T cell-derived approaches, including T cell membrane-coated nanoparticles, T cell-derived exosomes, T cell hitchhiking, and CAR-T cells. We discuss how these methods improve biodistribution, tissue penetration, and immune evasion while preserving T cell functionality in cancer therapies, autoimmune disorders, cardiovascular diseases, and infectious diseases. By comparing conventional nanomedicine approaches with emerging T cell-based delivery systems, this review explores the transformative capability of T cell-inspired delivery in enhancing therapeutic outcomes. Finally, we address current limitations and future directions, including advanced engineering techniques, which could further refine this promising approaches.
    Keywords:  CAR T cell therapy; Drug delivery; Nanomedicines; T cell
    DOI:  https://doi.org/10.1016/j.mtbio.2026.102909
  14. Crit Rev Oncol Hematol. 2026 Feb 22. pii: S1040-8428(26)00117-4. [Epub ahead of print]221 105230
    Roles of the gut microbiota in cancer immunotherapy: Mechanistic foundations and therapeutic opportunities.
    Qing-Lin Wu, Yi-Ran Zhou, Zi-Rong Chen, Ming-Xin Liu, Meng-Xin Liu, Yi-Fei Liu, Zhi-Shu Li, Qi-Rui Zhao, Yong-Qian Zhang, Guo-Qing Zhang, Zheng Zhang, Yu-Tong Gong, Can Tang, Tian Yang, Zu-Chao Du.
      Cancer immunotherapy has revolutionized oncological treatment through diverse modalities including immune checkpoint blockade, adoptive cell therapy, therapeutic vaccines, and cytokine-based approaches. Despite these advances, clinical responses remain heterogeneous, with sustained benefit limited to a minority of patients. Emerging evidence now implicates gut microbiota as a critical systemic regulator of immunotherapy efficacy across multiple treatment platforms, mechanistically linking intestinal dysbiosis to antitumor immunity through the gut-immune-tumor axis. Specific commensal taxa and their metabolites, including short-chain fatty acids and tryptophan derivatives, regulate anti-tumor immunity through effector T cell enhancement, dendritic cell activation, and regulatory T cell suppression. This review systematically examines the microbial-metabolite-immune axis, elucidating mechanisms whereby intestinal microbes and metabolites mediate immunotherapy responses. We comprehensively evaluate microbiota-targeting strategies including dietary interventions, probiotics, prebiotics, and fecal microbiota transplantation, providing mechanistic insights and translational frameworks. We further discuss current challenges in transitioning from associative microbiome studies to mechanistic causality, standardizing intervention protocols, and integrating multi-modal microecological data, proposing future directions for engineered probiotics and precision microbial therapeutics to optimize outcomes under current immunotherapy.
    Keywords:  Cancer immunotherapy; Gut microbiota; Microbialmetabolite-immune axis; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105230
  15. J Immunol Methods. 2026 Feb 21. pii: S0022-1759(26)00016-5. [Epub ahead of print]547 114040
    Immune cell separation for cell therapy: A comprehensive review of techniques, and challenges.
    Masoud Hassanzadeh Makoui, Amir Bayat Bodaghi, Mohammad Amin Razavi, Arman Taran, Amir Pooya Akbari, Mohammad Bahrami, Abdolreza Esmaeilzadeh.
      Cell-based immunotherapies, such as CAR-T and TIL therapies, represent a significant shift in the treatment of cancers and immune disorders. A critical first step in manufacturing these therapeutics is the efficient and selective isolation of specific immune cell populations (e.g., T cells, NK cells, and monocytes) from complex biological sources like peripheral blood or leukapheresis products. This comprehensive review systematically examines the current landscape of immune cell separation technologies that are essential for cell therapy manufacturing. We detail established methods, including density gradient centrifugation, magnetic-activated cell sorting (MACS), and fluorescence-activated cell sorting (FACS), as well as emerging techniques like microfluidics, acoustophoresis, and affinity ligand-based platforms. The review evaluates each technique based on key parameters: purity, yield, viability, processing time, scalability, cost-effectiveness, and compatibility with Good Manufacturing Practice (GMP) requirements. Furthermore, we emphasize the crucial role of rigorous post-separation characterization, which includes phenotypic analysis (flow cytometry), functional assessment (proliferation, cytokine release, cytotoxicity), and sterility testing to ensure product quality and safety. We thoroughly analyze significant challenges, such as the need for gentle processing to preserve cell function, achieving sufficient scalability for clinical and commercial production, minimizing process-induced cellular stress, reducing reagent costs (especially for antibody-based methods), navigating complex regulatory pathways, and establishing robust release criteria. This synthesis underscores that while considerable progress has been made, advancements in separation technologies, integrated characterization strategies, and standardized approaches are vital for overcoming existing bottlenecks and fully realizing the transformative potential of cell-based immunotherapies.
    Keywords:  Adoptive cell therapy; Cell separation; Flow cytometry; Immunomagnetic separation; Tissue-based therapy
    DOI:  https://doi.org/10.1016/j.jim.2026.114040
  16. Oncologist. 2026 Feb 25. pii: oyaf431. [Epub ahead of print]
    Ready or Not, Here They Come: A Practical Guide to Adoptive T cell Therapies for Solid Tumors for Medical Oncologists.
    Tuan Hoang, Sameena Khan, Adrian Sacher.
      Adoptive cell therapies (ACTs) include chimeric antigen receptors (CARs), bispecific T cell engagers (BiTES), tumor infiltrating lymphocytes (TILs) and T cell receptor (TCR) gene modified T cells. ACTs have significantly improved patient outcomes associated with hematologic malignancies. Recent advances have demonstrated their potential in solid tumors with promising clinical trial results signaling that they represent paradigm shift in oncologic care. As these therapies become standard care in solid tumors, medical oncologists must become adept at recognizing and managing their unique toxicities including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). This review synthesizes the latest clinical data on ACTs in solid tumors, highlighting key findings and toxicity profiles. In addition, the review provides an overview of early recognition and evidence-based management of CRS and ICANS. Equipping clinicians with the necessary knowledge to navigate toxicity management will be essential in optimizing patient outcomes as ACTs are increasingly adopted in solid tumor oncology.
    Keywords:  Adoptive cell therapy; Bispecific T cell engager (BiTE); CAR-T cell; Immune effector cell-associated neurotoxicity syndrome (ICANS); cytokine release syndrome (CRS); solid tumors
    DOI:  https://doi.org/10.1093/oncolo/oyaf431
  17. Cells. 2026 Feb 11. pii: 328. [Epub ahead of print]15(4):
    Stem Cell-Based Therapies in Autoimmune Diseases: Current Evidence, Unmet Needs, and Future Directions-A Closing Editorial Review.
    Györgyi Műzes, Ferenc Sipos.
      The long-lasting, varied, and complicated nature of immune system issues in autoimmune disorders continues to make treatment difficult. Although standard immunosuppressive and biologic therapies have enhanced disease management, they infrequently provide enduring remission and often result in cumulative damage. Due to this, stem cell treatment has emerged as a potential alternative that aims to restore immunological homeostasis rather than maintain long-term immune suppression. This editorial review provides a comprehensive overview of the current evidence, unmet requirements, and future directions in the field, summarizing the primary contributions of the Special Issue "Stem Cell Therapy for Autoimmune Diseases". We examine the conceptual distinction between immune reset, as demonstrated by hematopoietic stem cell transplantation, and immune modulation, which is facilitated by mesenchymal stromal cells and their secretome. Systemic sclerosis, neuroimmunological disorders, inflammatory bowel disease, and type 1 diabetes exhibit disease-specific clinical experiences that underscore both context-dependent limitations and therapeutic potential. Meanwhile, an urgent need to address persistent issues such as incomplete immune reconstitution, autoreactive memory cell-driven relapse, a lack of predictive biomarkers, safety concerns, and complex ethical and regulatory problems is addressed. This review concludes by offering perspectives on the future development of this approach, highlighting standardization, biomarker-driven patient selection, and next-generation techniques, including extracellular vesicles and genetically modified cells. This overview marks stem cell therapy as a crucial area of research for the treatment of autoimmune disorders.
    Keywords:  autoimmune diseases; immune modulation; immune reset; secretome; stem cell therapy
    DOI:  https://doi.org/10.3390/cells15040328
  18. Biomedicines. 2026 Jan 29. pii: 296. [Epub ahead of print]14(2):
    CAR T-Cell Immunotherapy in Neuroautoimmune Diseases: Focus on the Central Nervous System.
    Fotis Demetriou, Maria Anagnostouli.
      The treatment of central nervous system (CNS) autoimmune diseases has evolved from broad immunosuppression toward targeted disease-modifying therapies (DMTs). While current DMTs effectively control inflammatory activity in many patients, unmet needs remain, including persistent compartmentalised CNS pathology, limited tissue penetration, and the cumulative burden of chronic therapy. Chimeric antigen receptor (CAR) T-cell therapy represents a novel "living" immunotherapy capable of antigen-specific cellular depletion. Although currently approved only for B-cell malignancies, CAR T-cells are increasingly being explored in CNS autoimmunity leveraging their capacity for autonomous cytotoxicity and expected access to immune cells within protected CNS niches following a potentially single intervention. In this review, we examine CAR T-cells in the context of CNS-autoimmunity, we outline principles derived from oncologic applications, assess current DMTs, their limitations and side effects, and define parameters where CAR T-cells may offer added value. We discuss biological and practical requirements for broader clinical application, as currently they are investigated only for the very severe and refractory cases where all alternative treatments have failed. We further review the plasticity of CAR constructs, distinguishing clinically advanced platforms from early proof-of-concept approaches. Finally, we summarise clinical experience from 15 patients with CNS autoimmunity treated with CAR T-cells and review ongoing or planned trials that include such patients. We conclude that CAR T-cell therapy remains investigational for severe, treatment-refractory disease, with future applicability dependent on demonstrable efficacy, safety, cost, and feasibility beyond existing DMTs.
    Keywords:  B-cells; CAR T-cells; CNS autoimmunity; DMTs; HLA; MOGAD; MS; NMOSD; autoimmune encephalitis (AE)
    DOI:  https://doi.org/10.3390/biomedicines14020296
  19. Front Immunol. 2026 ;17 1769847
    Advances in T cell-based immunotherapy for osteosarcoma.
    Kun Zhang, Zheng Wang, Jiaqi He, Liuru Lu, Wenshu Wang, Aiwei Yang, Huayi Xie, Linhui Huang, Yuying Huang, Ke Zhang, Mingyang Jiang, Ruqiong Wei.
      Osteosarcoma, the most prevalent primary malignant bone tumor in children and adolescents, remains a formidable clinical challenge due to its high metastatic potential and limited therapeutic progress over the past three decades. While surgery combined with multi-agent chemotherapy has improved outcomes for patients with localized disease, prognosis for those with recurrent or metastatic osteosarcoma remains poor. Although immunotherapy has revolutionized cancer care across multiple malignancies, its efficacy in osteosarcoma has been modest, largely owing to an immunosuppressive tumor microenvironment, functional T cell exhaustion, and pronounced antigenic heterogeneity. Recent advances in T cell-based strategies, including MHC-independent γδ T cells, immune checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4, and chimeric antigen receptor (CAR) T cells directed against antigens such as HER2, GD2, and B7-H3, have demonstrated encouraging preclinical activity but limited clinical translation. Emerging evidence suggests that impaired antigen presentation, suppressive immune cell populations, and inadequate T cell trafficking collectively restrict therapeutic efficacy. This review summarizes recent mechanistic and translational advances in T cell-directed immunotherapy for osteosarcoma and proposes future directions to improve clinical outcomes.
    Keywords:  T cells; adaptive immunity; immune checkpoint inhibitors; immune evasion; immunotherapy; innate immunity; osteosarcoma
    DOI:  https://doi.org/10.3389/fimmu.2026.1769847
  20. J Mark Access Health Policy. 2026 Mar;14(1): 6
    Enhancing Patient-Centered Health Technology Assessment: A Modified Delphi Panel for PICOS Scoping in Spinal Muscular Atrophy.
    Emanuele Arcà, Adele Barlassina, Adaeze Eze, Valentina Strammiello.
       Highlights: What is the main finding? This paper illustrates how systematic PICOS scoping can be operationalized within JCAs through Delphi consensus methods for mapping and reconciling multiple national and patient perspectives into a common framework.It highlights concrete examples of harmonization and clarifies the methodological tensions that arise when balancing rigor with flexibility. What are the implications of the main findings? The findings underscore that early, structured stakeholder engagement-particularly involving patients-is essential for JCAs to be inclusive, scientifically robust, and relevant for national reimbursement decisions.Clear PICOS scoping could improve transparency while also enhancing the credibility and uptake of JCA outcomes in healthcare policy.
    Abstract: Objectives: This study explores the feasibility and value of integrating structured patient input into the PICOS (Population, Intervention, Comparator, Outcome, Study design) scoping process for Joint Clinical Assessments under the EU Health Technology Assessment Regulation. Methods: A modified Delphi panel, led by a steering committee composed of two clinicians, one patient expert, and one policy expert, engaged 12 individuals representing patient organizations across 12 European Member States to reach consensus on PICOS elements for CAR-T therapy in pediatric spinal muscular atrophy. Results: The Delphi process effectively facilitated PICOS consolidation and consensus among the 12 patient experts representing diverse EU contexts. Through 3 iterative rounds integrating quantitative rankings and qualitative feedback, the panel achieved strong agreement on key outcomes, intervention delivery, and study design elements, with population eligibility and comparator selection showing heterogeneity. Patient engagement was central: participants emphasized inclusive eligibility criteria, shared decision-making, and the inclusion of caregiver perspectives. The integration of qualitative insights allowed nuanced interpretation of dissent, distinguishing between genuine disagreement and framing effects, thereby enhancing transparency and scientific validity. Importantly, the process revealed patient priorities for outcomes, treatment burden, and evidence trade-offs, informing both PICOS refinement and future health technology assessment (HTA) strategies. This structured, participatory approach demonstrates the feasibility and value of incorporating patient voices systematically into early-stage EU HTA, fostering robust, credible, and context-sensitive consensus on complex rare-disease interventions. Conclusions: The study demonstrates the potential of consensus-building methodologies to enhance transparency, reduce heterogeneity, and support patient-centered evidence generation and decision-making in HTA.
    Keywords:  CAR-T therapy; Delphi consensus; EU HTAR; PICOS scoping; evidence synthesis; health technology assessment; patient engagement; spinal muscular atrophy; stakeholder engagement
    DOI:  https://doi.org/10.3390/jmahp14010006
  21. Front Mol Med. 2026 ;6 1763390
    CD19 exon 2 skipping is a potential prognostic correlate of anti-CD19 CAR-T therapy relapse.
    Søren Helweg Dam, Giorgia Moranzoni, Magnus Haraldson Høie, Signe Modvig, Karin A W Wadt, Bodil Als-Nielsen, Kjeld Schmiegelow, Kristoffer Vitting-Seerup, Mike Bogetofte Barnkob, Lars Rønn Olsen.
      Relapse following anti-CD19 chimeric antigen receptor (CAR) T cell therapy remains a concern in the treatment of refractory B-cell malignancies. Although the CD19Δexon2 splice variant has been linked to treatment failure, reliable pre-treatment biomarkers for relapse risk are lacking. Here, we analyzed RNA-sequencing data from a small publicly available cohort of four anti-CD19 CAR-T-treated B-cell acute lymphoblastic leukemia patients, including one responder, one non-responder, and two who relapsed after initial response. We quantified the percent spliced in (PSI) of CD19 exon 2, as a proxy for CD19Δexon2 abundance before and after treatment. The patient with the lowest pre-treatment exon 2 PSI (i.e., highest estimated abundance of CD19Δexon2) experienced the earliest relapse, whereas the complete responder showed no detectable exon 2 skipping. In silico protein structure modeling indicated reduced structural stability of the FMC63 epitope region in the CD19Δexon2 variant, supporting a potential mechanistic link between exon 2 exclusion and antigen escape. Analysis of larger RNA-sequencing datasets from CAR-T treatment-naïve B-cell malignancies and healthy tissues revealed low-level exon 2 skipping in some individuals across both malignant and normal B cells. These findings suggest that CD19 exon 2 skipping may correlate with relapse after CAR-T therapy, and its presence in treatment-naïve individuals highlights its potential for evaluation as an RNA- or qPCR-based biomarker in future studies.
    Keywords:  CAR T-cell therapy; CD19; isoform switching; relapse prediction; splice variant
    DOI:  https://doi.org/10.3389/fmmed.2026.1763390
  22. Exp Biol Med (Maywood). 2026 ;251 10938
    How can we balance risk and benefit of interleukin-18 armored T cell therapies?
    Paulina Vicenova, John Maher.
      CD19-specific CAR T cells engineered to secrete a constitutively active form of the pro-inflammatory cytokine, interleukin (IL)-18 have demonstrated impressive efficacy in a recent clinical trial involving subjects who had failed prior CAR T cell therapy. Corroborating these clinical data, preclinical studies of IL-18-armored CAR and T cell receptor-engineered T cells have demonstrated enhanced anti-tumor activity in several xenograft and syngeneic mouse cancer models. Interleukin-18 improves tumor clearance via direct effects on CAR T cells and indirect actions on cells on a variety of host immune cells, including natural killer, macrophage and dendritic cells. Compared to unarmored CAR T cells, IL-18-secreting CAR T cells are less exhausted, expand more efficiently and produce greater quantities of interferon (IFN)-γ. However, upregulated circulating IL-18 and its downstream mediator, IFN-γ, are also associated with systemic toxicities which have proven to be severe on occasions. In light of this, several groups have developed strategies that set out to restrict IL-18 release or biological activity to the tumor microenvironment. Among these, CAR T cells armored with NFAT-inducible IL-18 are now undergoing clinical testing. The evaluation of inducible or tumor-selective IL-18 deployment will show whether it is possible to minimize IL-18 related systemic toxicities while preserving localized amplification of anti-tumor activity.
    Keywords:  IL-18 binding protein (IL-18BP); T cell redirected for universal cytokine-mediated killing (TRUCK); TCR-engineered T cell; chimeric antigen receptor (CAR) T cell; cytokine release syndrome (CRS); interferon-γ (IFN-γ); interleukin-18 (IL-18); tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/ebm.2026.10938
  23. Discov Oncol. 2026 Feb 27.
    Next-generation CAR-T and CAR-NK cell therapies in hematologic malignancies: engineering for persistence, specificity, and safety.
    Mutaz Jamal Al-Khreisat, Waleed K Abdulsahib, Ihsan Khudhair Jasim, H Malathi, Priya Priyadarshini Nayak, D Alex Anand, Gunjan Mukherjee, Aashna Sinha, Norbek Kholboyev.
      
    Keywords:  CAR-NK cells; CAR-T cells; Genetic engineering; Hematologic malignancies; Immunotherapy
    DOI:  https://doi.org/10.1007/s12672-026-04731-9
  24. Front Immunol. 2026 ;17 1722590
    Human serum influences functional plasticity and transcriptomic landscape of γδ T cells in vitro.
    Lorraine Pinot, Zhibek Zhumadilova, Aylin Saßor, Sagar, José Villacorta Hidalgo.
      γδ T cells are emerging as a promising platform for adoptive cell therapy due to their ability to recognize tumors independently of MHC and their minimal risk of causing graft-versus-host disease. While serum-supplemented media have traditionally been used for T cell expansion, they can present limitations including xenogeneic contaminants and batch variability. These issues can compromise T cell phenotype, function, and clinical reproducibility. In this study, we evaluated the impact of human serum on the expansion, phenotype, function, and transcriptomic landscape of Vγ9Vδ2 γδ T cells cultured with zoledronate and cytokines under serum-free versus serum-containing conditions. We evaluated cytotoxicity against triple-negative breast cancer cell lines, activation and checkpoint marker expression, and cytokine secretion. Single-cell RNA and TCR sequencing revealed consistent differentiation trajectories across donors in both conditions and gene expression dynamics during a two-week expansion period. Our results show that serum-free culture supports robust γδ T cell expansion with higher purity and an activated phenotype marked by increased activation markers and reduced checkpoint receptor expression. Serum-free expanded cells displayed comparable or enhanced cytotoxicity and cytokine production, especially IFN-γ. TCR repertoire diversity was preserved without clonal skewing in both conditions. Furthermore, re-exposure to serum late in culture had minimal influence on γδ T cell functionality. These findings demonstrate the feasibility and advantages of serum-free expansion protocols for Vγ9Vδ2 γδ T cells, offering improved consistency, safety, and therapeutic potential.
    Keywords:  allogeneic; gamma-delta T cells; immunotherapy; serum-free medium; single-cell RNA sequencing
    DOI:  https://doi.org/10.3389/fimmu.2026.1722590
  25. Cell Transplant. 2026 Jan-Dec;35:35 9636897251374248
    A novel GMP-manufactured medicinal product candidate composed of NK and γδ T cells as adjunct immunotherapy for hematopoietic stem cell transplantation.
    Fabio Morandi, Martina Della Lastra, Gino Tripodi, Federica Sabatini, Claudia Cocco, Marco Risso, Roberto Gramignoli, Federico Zara, Irma Airoldi.
      γδ T lymphocytes and NK cells are effective to kill tumors or viral-infected cells avoiding graft versus host disease (GvHD), thus they have attracted high interest as potential tool for adoptive cell therapy. We generated an advanced therapy medicinal product (ATMP) composed of mature γδ T and NK cells to provide an innovative tool to protect patients against tumor relapse and life-threatening infection after haploidentical hematopoietic stem cell transplantation. The ATMP was manufactured and validated in a GMP facility and was obtained from leukapheresis stimulated with zoledronic acid and IL-2, afterward depleted of αβ T lymphocytes using the CliniMACS Prodigy. The ATMP is characterized by high homogeneity, cell viability, cytotoxic abilities, stability after cryogenic preservation, and it was virtually free of αβ T and B lymphocytes. Both NK and γδ T cells were activated and characterized by high expression of cytotoxic and activating receptors including NKG2D, CD16, NKp30, NKp44, and NKp46. Furthermore, γδ T lymphocytes and NK cells were cytotoxic against myeloid leukemia or neuroblastoma cells. In conclusion, we implemented a novel ATMP to be shortly translated into clinical practice, which may be used in the post-transplant phase as efficacious immunotherapy in neuroblastoma and leukemic pediatric patients.
    Keywords:  GMP; NK cells; advanced therapy medicinal product; γδ T lymphocytes
    DOI:  https://doi.org/10.1177/09636897251374248
  26. Pac Symp Biocomput. 2026 ;31 855-858
    Applications of AI & ML in Biomanufacturing of Cell and Gene Therapies.
    Eric Neumann, Karen Weisinger, Tom Londo.
      This workshop highlights how AI/ML technologies are beginning to be applied to biomanufacturing and bioengineering of cell and gene therapies (CGT). AI/ML have demonstrated their utility in biocomputing and biomedical research applications, and are poised to become central to design, scaling, and optimization of bioengineering processes such as CAR-T cells, iPSC, and biomolecule production. Invited speakers from academia and industry will speak of their experience in leveraging these new intelligent technologies.
    DOI:  https://doi.org/10.1142/9789819824755_0063
  27. Front Pharmacol. 2026 ;17 1715984
    Global Panoramic analysis of clinical research in cell therapy: clinical trial landscape, marketed products, and regulatory trends.
    Mengmeng Wang, Tiange Zhou, Sijia Liu, Wanwan Xiang, Kewen Xie, Xiaoqiong Zhang, Wenxin Hu, Mengling Fang, Ziyue Zhang, Meimei Chen, Xi Wang, Jiancai Wu.
       Introduction: Cell therapy is a vital field in modern medicine. This review assesses its global clinical development landscape, approved products, and regional regulatory characteristics.
    Methods: A comprehensive search and analysis of global clinical trial databases (e.g., https://clinicaltrials.gov/ClinicalTrials.gov), regulatory agency announcements, and relevant literature up to October 2025 was conducted. Key data points regarding trial numbers, phases, therapy types, and approved products were extracted and analyzed descriptively by region.
    Results: A cumulative total of 10,373 cell therapy clinical trials were identified worldwide, with primary distribution across the United States (3,563 trials), China (3,365 trials), and Europe (1,584 trials). Oncology (56.1%) and immune system diseases (9.3%) were the main research focuses. Immune cell therapy (5,167 trials) and stem cell therapy (4,796 trials) received comparable attention, with CAR-T therapy (2,409 trials) being prominent within the former, and mesenchymal stem cells (MSCs, 1,904 trials) and hematopoietic stem cells (HSCs, 1,550 trials) dominating the latter. Since 2016, China has led in the number of clinical trials, particularly in CAR-T research. Europe had a significantly higher proportion of Phase III trials compared to China and the US. The US led in the approval of HSC-based drugs. Approved immune cell drugs are predominantly CAR-T products for hematological malignancies, originating mainly from the US and China. Approved stem cell drugs are primarily HSC and MSC products, authorized in the US, Japan, South Korea, and China, covering indications such as graft-versus-host disease. Other somatic cell therapies are established for skin repair, bone disorders, and ophthalmology, with South Korea leading in skin-related products.
    Discussion: These findings reveal distinct regional strengths and strategic emphases in cell therapy development. The observed patterns are significantly influenced by heterogeneous regulatory frameworks across regions. The global industry is advancing the translation of cell therapy from cutting-edge technology to accessible clinical application through the synergy of scientific innovation and evolving regulatory pathways.
    Keywords:  CAR-T; cell therapy; clinical trials; marketed products; regulatory trends
    DOI:  https://doi.org/10.3389/fphar.2026.1715984
  28. J Control Release. 2026 Feb 24. pii: S0168-3659(26)00154-9. [Epub ahead of print] 114752
    Thermal sonogenetics for adoptive cell transfer therapy.
    Ana Baez, Kyle Hazel, Zakary Guertin, Ellen Fong, Megan Mc Manus, Alex Kaloyannis, Brandon Helfield.
      Adoptive cell transfer (ACT)-based immunotherapy has emerged as a transformative approach for treating cancer, offering durable responses through the ex vivo expansion and reinfusion of antigen-specific immune cells. Despite remarkable clinical successes, most notably with chimeric antigen receptor (CAR)-T cell therapy, ACT remains limited by severe toxicities such as cytokine release syndrome, on-target off-tumor effects, and suppression within the tumor microenvironment (TME). To address these challenges, there is growing interest in engineering immune cells with inducible gene circuits that enable spatially and temporally controlled activation. While small molecule- and light-inducible systems have demonstrated proof-of-concept control, their clinical translation is hindered by issues of pharmacokinetics, tissue penetration, and systemic exposure. Focused ultrasound (FUS) offers a non-invasive alternative capable of achieving localized and deep tissue heating, enabling precise activation of genetically engineered cells through heat-responsive promoters, a strategy termed thermal sonogenetics. This review summarizes recent advances in FUS-mediated, heat-inducible genetic control within the context of ACT-based immunotherapy. We first outline the development, successes, and limitations of current ACT platforms, including TIL, TCR-T, and CAR-T therapies, to motivate the need for controllable systems. We then discuss the use of heat shock promoters-particularly HSP70-family elements-as central components of thermal gene switches and review all benchtop and preclinical studies employing FUS for inducible gene expression in immune and non-immune cells; finally, we consider the future potential and limitations of thermal sonogenetics to enable remote, precise, and reversible control of engineered immune cells, paving the way for safer and more effective cellular immunotherapies.
    Keywords:  Acoustics; CAR-T cells; Focused ultrasound; High intensity focused ultrasound; Immunotherapy; Targeted therapy
    DOI:  https://doi.org/10.1016/j.jconrel.2026.114752
  29. Intractable Rare Dis Res. 2026 Feb 28. 15(1): 17-25
    Health technology assessment and medical insurance access for rare disease drugs in China: A policy review with quantitative insights from publicly available data.
    Dandan Ai, Binyan Sui, Chengaxin Duan, Zhao Liu, Fan Zhang, Kun Zhao.
      To ascertain the status and propose optimization strategies for rare disease drugs (RDDs) value assessment in the scenario of the National Reimbursement Drug List (NRDL) dynamic adjustment in China, we conducted a narrative policy review that synthesized published literature and policy documents, supplemented by a secondary descriptive statistical analysis of publicly available 2022-2024 year NRDL negotiation data to contextualize recent reimbursement practices for rare disease drugs in China. This study found that value assessment of RDDs largely aligned with the traditional framework, encompassing five key dimensions: safety, efficacy, economic evaluation, innovation, and equity. Considering disease severity and the competitive landscape, innovative RDDs tend to receive higher clinical value ratings, higher willingness-to-pay thresholds, and broader policy support across the healthcare system. Between 2022 and 2024, a total of 60 RDDs applied for NRDL inclusion, with 43% successfully reimbursed. Most applicants were either original research drugs already approved overseas or modified new drugs launched domestically and abroad. Notably, 42% of the drugs had achieved global first launches before 2015, thereby accumulating extensive clinical evidence, and 58% submitted randomized controlled trial (RCT) data. The proportion of drugs supported by RCT evidence in the reimbursed group was significantly higher than the figure in the non-reimbursed group, whereas the proportion of drugs with pediatric indications were relatively lower in the reimbursed group. No significant differences were observed in other value assessment dimensions between successful and unsuccessful applicants. It is recommended that China develop detailed health technology assessment (HTA) guidelines and real-world evidence (RWE) guidance tailored for RDDs, facilitating the generation of high-quality evidence and decreasing decision-making risks associated with the value assessment of innovative RDDs.
    Keywords:  health technology assessment; marketing access; medical insurance reimbursement; rare disease
    DOI:  https://doi.org/10.5582/irdr.2025.01076
  30. Transfusion. 2026 Feb 23.
    Cord blood in a rapidly evolving biotherapies landscape.
    Jessica M Sun, Joanne Kurtzberg.
      Since the identification of hematopoietic stem cells (HSCs) in umbilical cord blood (CB) by Broxmeyer in the 1980s,1 the primary clinical use of CB remains as an unrelated donor source for hematopoietic stem cell transplantation (HSCT). However, the presence of additional progenitor cells and growth factors in CB and cord tissue also makes them readily available sources of cells and biomaterials potentially suitable for use as starting material to manufacture a wide range of evolving biotherapies. CB banks, with their existing infrastructure and readily available inventory of fully characterized CB units, are well-positioned to contribute to the development and implementation of CB and cord-tissue based biotherapies.
    DOI:  https://doi.org/10.1111/trf.70112
  31. J Microbiol. 2026 Jan;64(1): e2510017
    Development of tri-cistronic CLDN18.2 CAR-T cells incorporating PD-1/CD28 switch and cyclophilin A for enhanced solid tumor immunotherapy.
    Heon Ju Lee, Seo Jin Hwang, Eun Hee Jeong, Mi Hee Chang, Bu Yeon Heo, Jaeyul Kwon, Yoona Noh, Jihoon Nah.
      Chimeric antigen receptor (CAR)-T cell therapy holds significant potential for the treatment of solid tumors. However, immune suppression and tumor-specific barriers limit its application. Claudin 18.2 (CLDN18.2), a gastric lineage-specific tight junction protein highly expressed in gastric and pancreatic cancers, is a promising therapeutic target. In this study, we aimed to develop a next-generation tri-cistronic CLDN18.2-directed CAR-T cell platform that integrates a programmed cell death protein 1 (PD-1)/CD28 chimeric switch receptor with cyclophilin A (CypA). This platform sought to counteract PD-1-mediated immunosuppression and enhance T-cell activation and persistence. We generated CLDN18.2 CAR-T cells incorporating costimulatory inducible T-cell costimulator (ICOS) domains using lentiviral vector-based recombinant engineering. We further evaluated their cytokine release, cytotoxic activity, and safety profiles. In vitro, tri-cistronic CAR-T cells exhibited markedly increased interferon γ and tumor necrosis factor α secretion and enhanced cytotoxicity against CLDN18.2-positive gastric cancer cells compared with conventional CAR-T constructs. In vivo, these cells showed superior antitumor efficacy and sustained tumor regression without observable toxicity in xenograft gastric cancer models. Collectively, these findings demonstrate that the integration of PD-1/CD28 signaling and CypA within a tri-cistronic framework significantly reinforces CAR-T cell functionality and durability. This suggests strong clinical potential as a next-generation immunotherapy for solid tumors.
    Keywords:  Claudin18.2 (CLDN18.2) antigen; PD-1/CD28 chimeric switch receptor; cyclophilin A (CypA); gastric cancer; immune checkpoint modulation; tri-cistronic CAR-T cells
    DOI:  https://doi.org/10.71150/jm.2510017
  32. Int J Nanomedicine. 2026 ;21 582804
    Engineering Kidney-Targeted Drug Delivery Systems: Principles, Materials, and Emerging Strategies.
    Shaogang Wang, Na Zeng, Yuhan Wang, Yuanyuan Yang.
      Kidney-targeted drug delivery is pivotal for treating renal diseases while minimizing systemic toxicity. To navigate the organ's complex physiological barriers, advanced nanomedicines employ integrated strategies. Our comprehensive narrative review provides a structured analysis of these strategies through a dual lens: first, by examining the fundamental mechanisms of renal targeting-including passive filtration, active receptor-mediated uptake, and their synergistic combination; and second, by deconstructing delivery systems into several fundamental pillars, the carrier platforms, the functional moieties that confer targeting, responsiveness and special properties along with therapeutic cargo. We evaluate how polymeric nanoparticles, liposomes, and exosomes, when functionalized with peptides, antibodies, or biomimetic coatings, can achieve enhanced renal specificity. Furthermore, we discuss how microenvironmental triggers such as pH, reactive oxygen species, and enzymes enable precise spatiotemporal drug release at pathological sites. Despite significant progress, critical translational challenges remain, including overcoming hepatic sequestration, ensuring long-term biocompatibility, and addressing patient heterogeneity. Future advances will depend on combining multimodal targeting, real-time feedback, and scalable manufacturing processes. This review synthesizes current knowledge to offer a rational design framework for the next generation of intelligent kidney-targeted therapeutics.
    Keywords:  kidney-targeted drug delivery; smart nanocarriers; stimuli-responsive release; synergistic targeting strategies
    DOI:  https://doi.org/10.2147/IJN.S582804
  33. Front Immunol. 2026 ;17 1735735
    PhIP-Seq: unveiling the complexity of antibody repertoires in health and disease.
    Wenjie Tang, Qijing Gai, Junjie Yang, Jianqing Chen, Zhengbing Lyu.
      Phage-Immunoprecipitation Sequencing (PhIP-Seq) merges phage display with next-generation sequencing to enable high-throughput profiling of antibody repertoires. This review synthesizes the technical evolution of the PhIP-Seq platform, critically assessing the workflow from peptide library design and immunoprecipitation to bioinformatics analysis. We evaluate strategies for optimizing library diversity and minimizing non-specific binding, while addressing inherent limitations such as the detection of conformational epitopes and post-translational modifications. The clinical utility of PhIP-Seq is examined through its application in identifying novel autoantigens in systemic lupus erythematosus and multiple sclerosis, mapping viral epitopes in SARS-CoV-2 and Plasmodium falciparum, and detecting tumor-associated antigens. Finally, we discuss the trajectory of the field toward integration with multi-omics datasets and the development of point-of-care diagnostic tools.
    Keywords:  PhIP-Seq; autoimmune diseases; cancer immunology; infectious diseases; phage display
    DOI:  https://doi.org/10.3389/fimmu.2026.1735735
  34. Biomolecules. 2026 Feb 04. pii: 246. [Epub ahead of print]16(2):
    Advances in Next-Generation Immunotherapies for Ovarian Cancer: Mechanisms of Immune Evasion and Novel Therapeutic Targets.
    Md Ataur Rahman, Maroua Jalouli, Mohammed Al-Zharani, Abdel Halim Harrath.
      Ovarian cancer (OC) is a particularly lethal gynecological malignancy with few treatment options due to its late-stage diagnosis, extensive genetic heterogeneity, and frequent development of resistance to existing therapies. Immunotherapy has revolutionized the management and clinical outcome of numerous solid tumors, but its clinical benefit for OC has been limited, in part due to an extremely immunosuppressive tumor microenvironment (TME) and diverse, overlapping immune evasion mechanisms. In this review, we present a comprehensive and timely synthesis of next-generation immunotherapeutic approaches for ovarian cancer, emphasizing strategies that overcome the immunosuppressive tumor microenvironment and improve clinical responsiveness. We describe the emerging molecular mechanisms of immune evasion in OC, including altered antigen presentation, inhibition of T-cell activation (e.g., via immunological checkpoints, metabolic reprogramming), polarization of tumor-associated macrophages (TAMs), and dysfunction of natural killer (NK) cells. We also critically examine several emerging therapeutic approaches, including combination immune checkpoint blockade (ICB), bispecific T-cell engagers (BiTEs), neoantigen-based vaccines, chimeric antigen receptor (CAR)-T- and CAR-NK-cell therapies, oncolytic viruses (OVs), and nanoparticle-mediated immunomodulation. In addition, we highlight recent advances in tumor microenvironment-targeted therapies for ovarian cancer, focusing on strategies that modulate non-lymphoid components such as cancer-associated fibroblasts (CAFs), hypoxia-driven signaling, and the PI3K/AKT/mTOR axis to enhance antitumor immune responsiveness. Finally, we discuss how predictive biomarkers, multi-omics systems, and patient-derived organoid models are accelerating the development and deployment of precision immunotherapies for OC. We would like to highlight the translational promise of next-generation immunotherapies and identify novel molecular targets that may be leveraged to achieve durable responses in OC.
    Keywords:  immune evasion; immunosuppressive; immunotherapy; next-generation therapeutics; ovarian cancer; tumor microenvironment
    DOI:  https://doi.org/10.3390/biom16020246
  35. Pharmaceutics. 2026 Feb 14. pii: 242. [Epub ahead of print]18(2):
    Pulmonary Drug Delivery for Infectious Diseases: Cutting-Edge Formulations and Manufacturing Technologies.
    Brayan J Anaya, Emanuel Osorio-Vargas, Samir Monterrosa-Moreno, Diego F Tirado, Elena González-Burgos, Dolores R Serrano.
      Pulmonary drug delivery has emerged as a powerful strategy for the treatment of respiratory infectious diseases, including bacterial, fungal, and viral infections such as influenza and COVID-19, by enabling high local drug concentrations while minimizing systemic exposure. However, the clinical success of inhaled anti-infective therapies critically depends on the precise engineering of particle properties that govern lung deposition, cellular targeting, and therapeutic efficacy. In this review, we provide a comprehensive and technology-driven overview of cutting-edge formulation and manufacturing strategies for pulmonary drug delivery, with particular emphasis on the key process and formulation parameters required to generate effective inhalable systems for the treatment of infectious diseases. Advanced particle-engineering approaches, including spray drying, spray freeze drying, jet milling, and supercritical fluid technologies are discussed as enabling tools to tightly control aerodynamic particle size, morphology, and solid-state properties. In parallel, emerging platforms such as nanoparticle-based delivery systems are examined for their ability to target specific lung cell populations, including epithelial cells and alveolar macrophages, thereby enhancing antimicrobial efficacy. Finally, innovative manufacturing concepts such as microfluidics and three-dimensional (3D) printing are highlighted as promising strategies to improve particle size uniformity, reproducibility, and formulation customization. By integrating formulation science with advanced manufacturing technologies, this review identifies the critical design and processing parameters that underpin effective pulmonary delivery of anti-infective therapies and outlines future directions for the development of next-generation inhaled treatments.
    Keywords:  3D printing use in lung therapy; aerodynamic properties; infectious respiratory diseases; lung-on-a-chip; particle engineering; pulmonary drug delivery
    DOI:  https://doi.org/10.3390/pharmaceutics18020242
  36. J Biosci. 2026 ;pii: 4. [Epub ahead of print]51
    Re-imagining T-cell receptor signaling: parallel paths may be key to discriminatory power.
    Akshay Tiwari, Narendra M Dixit.
      T-cells are important arms of our immune system and are central to our fight against pathogens and cancers (Baral et al. 2019a; Waldman et al. 2020). They recognize infected and cancerous cells and help destroy them while leaving uninfected/normal cells intact. They accomplish this tricky task with exquisite precision. How they do so has been an enigma and the subject of intense investigation for decades (Chakraborty and Weiss 2014; Courtney et al. 2018).
  37. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2026 Mar-Apr;18(2):18(2): e70053
    Drug Product Development of Lipid Nanoparticle-Based mRNA Therapeutics and Vaccines.
    Gideon Kersten, Eleonora Cerasoli, Bruce Kerwin, Olivia M Merkel, Andrea Hawe.
      Lipid nanoparticles (LNP) are currently the most relevant non-viral delivery systems for mRNA and occasionally for smaller nucleic acids such as small interfering RNA. Although the manufacturing of LNP is well established and scalable equipment is available for production, LNP drug product development is not straightforward. Numerous factors influence product quality, including LNP composition, process parameters, and formulation composition. A proper understanding and control of the critical variables is essential for product development of LNP containing pharmaceuticals. This article provides an overview on the drug product development roadmap for LNP-based therapeutics and vaccines. Based on the quality target product profile and current scientific and technical knowledge, key aspects that may impact product quality will be discussed. Strategies to identify failure risks as early in the development process as possible and ways to mitigate them will be addressed. The majority of steps in the development are covered, including LNP design and LNP manufacturing process, analytical development, and formulation development to achieve a stable and safe product suitable for human application. This article is categorized under: Biology-Inspired Nanomaterials > Lipid-Based Structures.
    Keywords:  drug product development; lipid nanoparticles; mRNA; nanomedicines; pharmaceutical development
    DOI:  https://doi.org/10.1002/wnan.70053
  38. Children (Basel). 2026 Feb 20. pii: 293. [Epub ahead of print]13(2):
    Personalizing Nutritional Therapy in Pediatric Oncology: The Role of Gut Microbiome Profiling and Metabolomics in Mitigating Mucositis and Enhancing Immune Response to Chemotherapy.
    Piotr Pawłowski, Natalia Zaj, Kamil Iwaniszczuk, Izabela Grzelka, Wojciech Makuch, Emilia Samardakiewicz-Kirol, Aneta Kościołek, Marzena Samardakiewicz.
       INTRODUCTION: Intensive chemotherapy protocols and hematopoietic stem cell transplantation (HSCT) in children with cancer frequently lead to severe complications, such as mucositis and immune dysfunction. A growing body of evidence indicates that these complications are closely associated with the patient's nutritional status and the composition of the gut microbiome, which becomes profoundly destabilized as a result of cytotoxic therapy and antibiotic use.
    BACKGROUND: The aim of this review is to critically evaluate the current state of knowledge on the interplay between gut dysbiosis, metabolomic profiles-with particular emphasis on short-chain fatty acids (SCFAs)-and treatment-related toxicity in pediatric patients, as well as to delineate pathways toward personalized nutritional therapy.
    METHODS: A narrative review was conducted, including clinical and preclinical studies published between January 2015 and October 2025. PubMed/MEDLINE, Embase, Cochrane Library, and other databases were searched, focusing on changes in microbiome composition, correlations between gut-derived metabolites and the severity of complications (sepsis, graft-versus-host disease [GvHD], mucositis), and the effects of targeted nutritional interventions (probiotics, prebiotics, postbiotics, and fecal microbiota transplantation [FMT]) on microbiome modulation during anticancer therapy.
    RESULTS: The analysis demonstrates that pediatric oncologic treatment leads to a marked reduction in microbial diversity, including the loss of protective Clostridiales taxa (e.g., Faecalibacterium), accompanied by an overgrowth of Proteobacteria pathobionts. Metabolomic profiling indicates that low SCFA levels (e.g., butyrate < 20-50 µmol/g) are a strong predictor of severe mucositis, prolonged neutropenia, and an increased risk of sepsis. Interventions aimed at restoring eubiosis and enhancing SCFA production show potential in strengthening the intestinal barrier, modulating immune responses, and enabling maintenance of the planned relative dose intensity (RDI) of chemotherapy by reducing treatment-related toxicity.
    CONCLUSIONS: Gut microbiome profiling and fecal metabolomics represent promising prognostic tools in pediatric oncology. There is an urgent need for further research employing "omics"-based approaches to develop precise, individually tailored nutritional protocols. Such strategies, including postbiotics and FMT, may minimize treatment-related adverse effects and improve long-term clinical outcomes in pediatric patients.
    Keywords:  dietary interventions; gut microbiome-targeted therapies; nutrition supplements; pediatric oncology
    DOI:  https://doi.org/10.3390/children13020293
  39. Front Med (Lausanne). 2026 ;13 1732164
    Progress in sepsis prediction models: from traditional scoring systems to multimodal intelligence and clinical translation.
    Chenglin Mou, Jinbin Yang, Qingmei Wu, Lian Qin, Junyu Lu.
      Sepsis is a leading cause of mortality and healthcare expenditures among patients in the intensive care unit (ICU). Its pathophysiology is complex and its clinical manifestations are highly heterogeneous; early identification and timely, targeted interventions are essential to improving outcomes. With the widespread adoption of electronic health records (EHRs) and the rapid expansion of critical care data, developing sepsis prediction models using machine learning (ML) and deep learning (DL) has become an active area of research. This review provides a systematic overview of advances in sepsis prediction, from clinical problem framing and outcome definitions to data sources, feature engineering, and methodological evolution. We summarize the progression from traditional scoring systems (e.g., SOFA, qSOFA) to modern ML algorithms (e.g., gradient boosting trees, random forests) and time series DL models (e.g., LSTM, Transformer models). We also outline reporting and evaluation standards (e.g., TRIPOD AI), and synthesize evidence on representative models for early warning, prognostic risk stratification, and prediction of organ dysfunction. Key translational challenges are discussed, including generalization, fairness, model drift, workflow integration, alarm fatigue, and real world utility. Finally, we highlight opportunities in multimodal data fusion, causal inference, federated learning, and digital twins for building next generation, clinically actionable sepsis intelligence, and we offer practical recommendations to help move from algorithmic accuracy to demonstrable clinical value, emphasizing that only models that are externally validated, well calibrated, prospectively evaluated, and tightly aligned with clinical workflows are likely to improve patient outcomes.
    Keywords:  clinical decision support; deep learning; machine learning; multimodal data; prediction models; sepsis; translational medicine
    DOI:  https://doi.org/10.3389/fmed.2026.1732164
  40. J Clin Med. 2026 Feb 15. pii: 1540. [Epub ahead of print]15(4):
    From Promise to Practice: Harmonizing Telemedicine in Pediatric Chronic Respiratory Diseases.
    Susanna Esposito, Daniele Donà, Giulia Brigadoi, Beatrice Rita Campana.
      Telemedicine has the potential to substantially improve the care of children and adolescents with chronic respiratory diseases, including asthma, cystic fibrosis, bronchiectasis, and chronic respiratory failure. Digital health interventions-such as remote monitoring, virtual consultations, adherence-support tools, and educational platforms-can enhance disease control, continuity of care, and access to specialized services. Despite these opportunities, the implementation of telemedicine in pediatric respiratory care remains fragmented and uneven across healthcare systems. A central barrier to progress is the marked heterogeneity of outcome measures used to evaluate telemedicine interventions. Inconsistent definitions, variable endpoints, and limited follow-up reduce comparability across studies, hinder evidence synthesis, and impede translation into clinical guidelines, reimbursement models, and policy decisions. Consequently, telemedicine is often confined to isolated pilot projects rather than embedded within standard care pathways. This narrative review issues a Call to Action for the coordinated implementation and harmonization of telemedicine in pediatric chronic respiratory diseases. We advocate for the urgent development and adoption of a Core Outcome Set (COS) to standardize outcome measurement across clinical trials and real-world evaluations. In addition, we highlight the importance of integrating implementation science, economic evaluation, ethical oversight, and equity considerations into telemedicine research and deployment. Addressing regulatory fragmentation, ensuring interoperability, and aligning accreditation with reimbursement and Health Technology Assessment requirements are essential for sustainable scale-up. Finally, we emphasize the need for international collaboration among clinicians, researchers, policymakers, payers, technology developers, and patient advocacy groups to accelerate learning and promote equitable, evidence-based digital care models. Through coordinated action, telemedicine can evolve from a promising innovation into a reliable and accessible standard of care for children with chronic respiratory diseases.
    Keywords:  chronic respiratory diseases; core outcome set; health equity; implementation science; pediatrics; telemedicine
    DOI:  https://doi.org/10.3390/jcm15041540
  41. Front Immunol. 2026 ;17 1730575
    Global trends of peripheral immune tolerance research: a bibliometric and visualization analysis.
    Shixiao Kong, Chen Lin, Yuting Shen, Jun Chen.
       Background: Peripheral immune tolerance is a key mechanism for maintaining immune homeostasis and preventing autoimmune responses. Although numerous studies have explored its molecular and cellular basis, a comprehensive and systematic overview of the field is still lacking. This study aims to elucidate the global research landscape of peripheral immune tolerance through bibliometric analysis.
    Methods: Publications related to peripheral immune tolerance from 1989 to 2025 were retrieved from the Web of Science Core Collection and Scopus databases. After removing duplicates, a total of 3,098 papers were included. CiteSpace, VOSviewer, RStudio Biblioshiny, and OriginPro were used for systematic analysis, allowing effective identification of research trends and emerging topics.
    Results: Since the 1990s, the annual number of publications on peripheral immune tolerance has steadily increased, peaking in 2008 before showing a slight decline. High-frequency keywords included autoimmunity, tolerance, and regulatory T cells. The United States, Germany, China, and Japan were the leading contributors, with Harvard University ranking first in both publication volume and citation frequency. Highly cited landmark papers by Sakaguchi, Freeman, and Curiel laid the theoretical foundation for the field. The Journal of Immunology had the highest publication count, while Nature Immunology showed the greatest impact.
    Conclusion: This study provides the first comprehensive bibliometric analysis of global research on peripheral immune tolerance, revealing the evolution of research themes over the past three decades and forecasting future trends. The findings offer valuable data support and insights for advancing research in this field.Systematic review registration.
    Keywords:  bibliometric analysis; immune regulation; peripheral immune tolerance; regulatory T cells (Tregs); research hotspots; research trends
    DOI:  https://doi.org/10.3389/fimmu.2026.1730575
  42. Cells. 2026 Feb 23. pii: 380. [Epub ahead of print]15(4):
    Determinants of Efficacy and Optimization of Chimeric Antigen Receptor T-Cell Therapy for Treating Multiple Myeloma: Current Status and Future Perspectives.
    Hiroshi Yasui, Noriko Doki, Wei Yan, Kohzoh Imai, Tadao Ishida.
      Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of relapsed and refractory multiple myeloma (MM), with BCMA-directed products demonstrating unprecedented response rates in heavily pretreated patients. Despite these advances, variabilities in response durability, treatment-related toxicities, and the emergence of resistance underscore the need for strategies that extend beyond CAR construct design alone. Accumulating evidence has indicated that the therapeutic outcomes of this approach are determined by a complex interplay between tumor burden, antigen dynamics, CAR T-cell functional fitness, and host immune context at the time of infusion. Effector-to-target balance and antigen load, in particular, have emerged as modifiable biological determinants of efficacy and safety, with pre-infusion disease control and response to bridging therapy exerting a profound influence on post-infusion CAR T-cell expansion, persistence, and clinical outcomes. Soluble BCMA (sBCMA) has also gained increasing attention as a practical biomarker that integrates tumor burden and antigen dynamics to facilitate the biologically informed optimization of treatment timing and patient selection. In addition to tumor- and antigen-related factors, the intrinsic properties of CAR T-cell products-including the spatial organization and clustering of CAR molecules on the T-cell surface-represent an additional layer of biological determinants that correlate with treatment responses. The quantitative functional assessment of CAR T-cell products may complement conventional clinical and tumor-based biomarkers and improve the prediction of therapeutic potency prior to infusion. This review summarizes recent advances in CAR T-cell therapy for treating MM, focusing on key mechanisms of resistance, the optimization of pre-infusion disease control, the integration of biological markers into clinical decision-making, and emerging combinations and sequential strategies. We also propose a design-oriented and patient-centered framework that integrates CAR engineering with disease biology and host immune factors to enhance the consistency, durability, and safety of CAR T-cell therapy. Such biologically guided optimization strategies will likely prove critical for fully realizing the transformative potential of CAR T-cell therapy across the evolving treatment continuum of MM.
    Keywords:  B-cell maturation antigen; biomarkers; bridging therapy; chimeric antigen receptor T-cell therapy; multiple myeloma; resistance; soluble B-cell maturation antigen; tumor burden
    DOI:  https://doi.org/10.3390/cells15040380
  43. Int J Nanomedicine. 2026 ;21 579975
    Red Blood Cell-Derived Extracellular Vesicles for Gene and RNA Therapeutics: Biological, Engineering, and Translational Challenges.
    Tayyab Shafiq, Nawaz Khan, Tehreem Kausar, Waqas Ahmed, Zihao Zhang, Yujie Liang, Li Duan.
      Gene therapy has great prospects of DNA/RNA manipulations and protein modulations. Its use in clinic is, however, stifled by risks of immunogenicity, low target specificity, and adverse effects. The red blood cell (RBC-EVs) extracellular vesicles can serve as a solution to this issue since they are biocompatible, long-term stable, and with low immunogenicity. RBC-EVs permit the accurate delivery of therapeutic cargo to space and time, thus minimizing systemic toxicity. This review presents the most recent developments on the expansion of the use of RBC-EVs to encapsulate the components of mRNA and CRISPR-Cas. Through the addition of the means to address these deficiencies, including stimulus-sensitive release mechanisms (eg, pH- or light-activated systems) and tissue-selective targeting approaches, RBC-EVs can be applied to enable the precise application in genetic diseases, inflammatory diseases, and cancer. Such innovations have the potential to overcome the clinical need and enable the biological complexity of mRNA- and CRISPR-Cas-based agents to provide a powerful delivery platform. Moreover, the review also demonstrates the unprecedented benefits of red blood cell EVs, which include immune evasion, scalability, and universal loading capacity, which can establish them as the next-generation delivery vehicles. Red blood cell EVs have the potential to increase the efficacy of precision medicine by increasing its feasibility. Lastly, we note the potential and translational issues in the provision of red blood cell EV-based mRNA and CRISPR-Cas therapeutic delivery of gene therapy.
    Keywords:  CRISPR-Cas; delivery vehicles; mRNA therapeutics; red blood cell-derived extracellular vesicles; targeting strategy
    DOI:  https://doi.org/10.2147/IJN.S579975
  44. Nurs Rep. 2026 Jan 27. pii: 42. [Epub ahead of print]16(2):
    Nursing Informatics and Undergraduate Nursing Curricula: A Scoping Review.
    Lisa Reid, Didy Button, Katrina Breaden, Mark Brommeyer.
      Introduction: Nursing informatics aims to improve patient care through rapid access to patient data, systematic assessment, a reduction in clinical errors, evidence-based practice, cost-effectiveness, and improved patient outcomes and safety. Background: Despite being the largest workforce in healthcare, nurses are not being adequately prepared to use nursing informatics, and this has been attributed to poor digital literacy, limited professional development, and a lack of undergraduate informatics education. Objectives: This scoping review aims to review contemporary published literature on the benefits, barriers, and enablers for embedding nursing informatics into undergraduate nursing education with a focus on the Australian healthcare context. Methods: A scoping review was conducted using the PRISMA-ScR checklist and the JBI Manual for evidence synthesis in adherence with an a priori scoping review protocol. A comprehensive search of JBI, Cochrane, CINAHL, Ovid, ProQuest, PubMed, and Scopus databases was performed. Two reviewers independently screened the results via Covidence, with discrepancies resolved via a third reviewer. Results: Two searches were conducted for this scoping review. In the first search, a total of 3227 articles were identified through database searches, with an additional 76 articles identified through bibliographic and grey literature searches. Following duplicate removal and screening, 46 articles met the inclusion criteria. In the second search, a total of 1555 articles were identified, and after duplicate removal and screening, 16 articles met the inclusion criteria. Duplicate removal during the second search round included those articles identified in the first search. The combined searches resulted in a total of 62 sources for this review. Conclusions: Despite the early adoption of nursing informatics in Australia in the 1980s, barriers remain to effective nursing informatics engagement and proficiency, including a lack of understanding of nursing informatics, limited infrastructure and resources, inadequate digital literacy of students and faculty, and the evolving nature of nursing informatics. Definitions of nursing informatics and associated fields, development of university faculty competency, access to digital health technologies, competency standards, digital literacy of the student cohort, faculty digital proficiency, and leadership from professional nursing bodies are all viewed as integral foundations for the development of student competency in nursing informatics.
    Keywords:  digital health; nursing education; nursing informatics; workforce readiness
    DOI:  https://doi.org/10.3390/nursrep16020042
  45. AAPS J. 2026 Feb 24. pii: 65. [Epub ahead of print]28(2):
    The Need for Clinical Trial Dataset Specifications to Support Clinical Pharmacology Review of Immunogenicity.
    Sophie Shubow, Mohsen Rajabi Abhari, Anh Ta, Jeffry Florian, Peter Lee, Yow-Ming C Wang.
      Assessment of product immunogenicity in clinical trials via characterization of the anti-drug antibody (ADA) response to the drug, is an important component of biological license applications (BLA). The clinical pharmacology review of immunogenicity focuses on the impact of ADA on pharmacokinetics (PK) based on data from three analysis datasets: Analysis Dataset (AD) for Subject Level data (ADSL), AD for Pharmacokinetic Concentrations (ADPC), and AD for Immunogenicity Specimens (ADIS). These datasets are derived from tabulation datasets that conform with the Clinical Data Interchange Standards Consortium (CDISC) Study Data Tabulation Model (SDTM) as requested by FDA and follow the CDISC Analysis Data Model (ADaM). Because no guidance is available on how to derive the ADIS dataset from the SDTM IS domain, BLAs submitted to the Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) vary in the completeness and quality of their ADIS datasets. This challenge has been addressed by information requests that can extend time of the clinical pharmacology review of immunogenicity. We analyzed the availability and content of ADIS, ADPC, and ADSL datasets in 48 BLAs submitted to CDER between 2019 and 2022. 75% of BLAs had at least one type of dataset issue. 50% of all BLAs had data reporting issues specifically (data format issues and/or missing data), 17% had data structure issues (where immunogenicity data were not reported in the dataset where the reviewer expected it, and/or a dataset does not follow the ADaM basic data structure), and 8% had more than one type of dataset issue. Our findings suggest that the publication of clinical trial dataset specifications to support the clinical pharmacology review of immunogenicity data could improve the efficiency of the regulatory review of CDER BLAs.
    Keywords:  CDISC; clinical pharmacology; data harmonization; immunogenicity; pharmacokinetics
    DOI:  https://doi.org/10.1208/s12248-026-01210-5
  46. Pharmaceutics. 2026 Feb 01. pii: 192. [Epub ahead of print]18(2):
    Recent Advances in Nanoparticle-Based Drug Delivery Strategies to Cross the Blood-Brain Barrier in Targeted Treatment of Alzheimer's Disease.
    Hoa Le, Giang T T Vu, Amos Abioye, Adeboye Adejare.
      The blood-brain barrier (BBB) is a major obstacle to the development of brain-targeted drug delivery systems, restricting greater than 98% of small molecules (<500 Da) and virtually all large-molecule drugs from entering the brain tissues from the bloodstream, resulting in suboptimal drug doses and therapeutic failure in the treatment of Alzheimer's disease (AD). However, the advent of nanotechnology has provided significant solutions to the BBB challenges, enabling particle size reduction, enhanced drug solubility, reduced premature drug degradation, extended and sustained drug release, enhanced drug transport across the BBB, increased drug target specificity and enhanced therapeutic efficacy. In corollary, a library of brain-targeted surface-functionalized nanotherapeutics has been widely reported in the current literature. These promising in vitro, in vivo and pre-clinical results from the existing literature provide quantitative evidence for the relative clinical utility of each of the techniques, indicating remarkable capacity for brain-targeted carrier systems; many of them are still being tested in human clinical trials. However, despite the recorded research successes in drug transport across the BBB, there are currently no clinically proven medications that can slow or reverse the progression of AD because most of the novel therapeutics have not been successful during the clinical trials. Therefore, the main option for the treatment of AD is symptomatic treatment using cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists. Although these therapies help to alleviate symptoms of AD and improve patients' quality of life, they neither slow the progression of disease nor cure it. Thus, an effective disease-modifying therapy for the treatment of AD is an unmet clinical need. It is apparent that a deeper understanding of the structural complexity and controlling dynamic functions of the BBB in tandem with a comprehensive elucidation of AD pathogenesis are crucial to the development of novel nanocarriers for the effective treatment of AD. Therefore, this narrative review describes the contextual analysis of several promising strategies that enhance brain-targeted drug delivery across the BBB in AD treatment and recent research efforts on two major AD biomarkers that have revolutionized AD diagnosis, amyloid-beta plaques and phosphorylated tau protein tangle, as potential targets in AD drug development. This has led to the Food and Drug Administration (FDA)'s approval of two intravenous (IV) anti-amyloid monoclonal antibodies, Lecanemab (Leqembi®) and Donanemab (Kisunla®), which were developed based on the Aβ cascade hypothesis for the treatment of early AD. This review also discusses the recent shift in the Aβ cascade hypothesis to Aβ oligomer (conformer), a soluble intermediate of Aβ, which is the most toxic mediator of AD and could be the most potent drug target in the future for a more accurate and effective drug development model for the treatment of AD. Furthermore, various promising nanoparticle-based drug carriers (therapeutic nanoparticles) that were developed from intensive research are discussed, including their clinical utility, challenges and prospects in the treatment of AD. Overall, it suffices to state that the advent of nanotechnology provided several innovative techniques for overcoming the BBB and improving drug delivery to the brain; however, their long-term biosafety is a relevant concern.
    Keywords:  Alzheimer’s disease; amyloid-beta oligomer; amyloid-beta plaque; blood–brain barrier; brain-targeting ligands; drug transport; protofibrils; tau protein tangle; therapeutic nanoparticles; tight junctions
    DOI:  https://doi.org/10.3390/pharmaceutics18020192
  47. J Visc Surg. 2026 Feb 25. pii: S1878-7886(26)00015-9. [Epub ahead of print]
    Goodbye P<0.05. P-value is simply one item among many to gauge scientific evidence.
    Karem Slim, Chadli Dziri, Bob Occean.
      For a century P-value is routinely used in almost every research paper with a threshold of 0.05 to reject the null hypothesis. The aim of this short review was to discuss the validity of this arbitrary (yet sacred) threshold. The history of P-value shows that very quickly, practitioners had found a simple method that appealed to them, while statisticians saw no great need to curb this enthusiasm, which seemed consensual. However, heavy reliance on P-values is of concern because of potential misuse and misinterpretation. The main pitfalls of P<0.05 are the dichotomized approach with a black-or-white judgement, possible false positive results, lack of information about magnitude of the effect, clinical relevance, and use out of context. These pitfalls explain why several statisticians and researcher recommend abandoning, not the P-value itself but the threshold of 0.05 and the term "statistical significance". We are faced with a paradigm shift by demoting P-value from its threshold-screening role and using alternative tools such as Bayesian methods, effect size with confidence intervals, more stringent thresholds, pragmatic trials, and the minimal clinically important difference. This will require statisticians, researchers, publishers, and health care decision makers to radically change the way they interpret scientific data by abandoning century-old dichotomous analysis-a true revolution to come.
    Keywords:  Clinical research; P<0.05; Statistical significance; Statistics
    DOI:  https://doi.org/10.1016/j.jviscsurg.2026.02.005
  48. Semin Pediatr Surg. 2026 Feb 10. pii: S1055-8586(26)00005-3. [Epub ahead of print] 151583
    The fetal frontier: A review of current and emerging fetal therapies for genetic diseases.
    Colton G Brown, Marissa Ray, Marco Carpenter, Braxton Forde, Tarun Subramanian, Haley Temple, Shivendra Tenguria, Laura Galganski.
      Pivotal advancements in diagnostics have greatly improved early detection of disease in the fetus. Rapid diagnosis of prenatal disease, including many aneuploidies and single-gene disorders, is now possible. These capabilities present an opportunity for earlier interventions and involvement of multidisciplinary care for infants discovered to have genetic disorders. While advancements continue to be made surgically addressing anatomic pathologies, more recently, the scope of fetal medicine has expanded to include the treatment of genetic disease. This unique and growing group of conditions with potential prenatal therapeutic targets spans broadly to include inborn errors of metabolism, neurodegenerative disorders, hematologic conditions, and errors in hormone biosynthesis. Because many of these hereditary conditions begin exerting deleterious effects before birth, prenatal therapies are critical to minimize or potentially avoid postnatal consequences. Fetal treatments can leverage the benefits of early human development such as a selectively permissive blood-brain barrier and a naive immune system. These factors, along with a favorable vector-to-tissue mass ratio in the fetus, create ideal treatment conditions that are not present after birth. Together, improved prenatal diagnostics and safe minimally invasive approaches for the delivery of therapies in utero have opened a window to what was previously an inaccessible population: the fetal patient. This review summarizes current clinical strategies and emerging investigational approaches, including enzyme replacement, protein therapy, stem cell transplantation, and gene-targeted interventions.
    Keywords:  Fetal surgery; Fetal therapy; Gene therapy; Genetic disorders
    DOI:  https://doi.org/10.1016/j.sempedsurg.2026.151583
  49. Exp Hematol Oncol. 2026 Feb 26. pii: 30. [Epub ahead of print]15(1):
    In vivo CAR-T engineering: insights from the 2025 ASH annual meeting.
    Gelayol Asadi, Misagh Rajabinejad.
      In vivo chimeric antigen receptor (CAR)-T engineering is a prominent field of research in cancer immunology, in which vectors are used to reprogram endogenous T-cells into CAR-T cells. Viral and nonviral platforms presented at the 67th Annual Meeting of the American Society of Hematology (ASH) offer precise T-cell targeting and efficient CAR expression. Preclinical models demonstrated robust generation of CAR-T cells, potent tumor clearance, and strong clinical translational potential. However, certain limitations remained to be addressed in future studies. This correspondence summarizes the key findings from the meeting, discusses current translational challenges, and highlights future directions.
    Keywords:  Delivery platforms; In vivo CAR-T; Targeted therapies
    DOI:  https://doi.org/10.1186/s40164-026-00762-8
  50. Clin Epigenetics. 2026 Feb 21.
    Epigenetic modulation to overcome immune suppression in pancreatic cancer.
    Laura Drndakova, Lucia Juhasikova, Ivana Hlavenova, Verona Buocikova, Sara Durdiakova, Michal Mego, Milan Buc, Bozena Smolkova.
      Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, primarily due to its highly fibrotic and immunosuppressive tumor microenvironment (TME), which limits both drug delivery and immune cell infiltration. Epigenetic dysregulation plays a pivotal role in shaping these barriers by controlling transcriptional programs that govern tumor-immune interactions, stromal remodeling, and immune evasion.This review synthesizes current insights into the contribution of aberrant epigenetic mechanisms to PDAC progression and immune resistance. We outline how epigenetic alterations suppress antigen presentation, sustain immunosuppressive cell populations, such as regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, and upregulate immune checkpoint molecules across cancer and stromal compartments. Emerging evidence shows that epigenetic therapies targeting DNA methyltransferases, histone deacetylases, histone methyltransferases, or bromodomain proteins can restore tumor immunogenicity, reprogram cancer-associated fibroblasts, and promote cytotoxic T cell infiltration. Furthermore, combining epigenetic modulators with immune checkpoint blockade or targeted therapies has demonstrated the capacity to remodel the PDAC TME and convert immunologically 'cold' tumors into more responsive ones. Therefore, we also summarize key completed and ongoing clinical trials in PDAC and solid tumors, emphasizing outcomes and biomarker discoveries that support the translation of epigenetic-immunotherapy combinations into clinical practice. Finally, we discuss persistent challenges that impede progress, including poor drug penetration through the desmoplastic stroma, off-target effects and toxicity of epigenetic agents, tumor hypoxia, adaptive resistance, and the scarcity of physiologically relevant immuno-oncology models.Findings from preclinical and early clinical studies indicate that epigenetic reprogramming represents a promising avenue to overcome PDAC immunoresistance by reactivating antigen presentation, disrupting immunosuppressive cellular networks, and enhancing antitumor immunity. However, realizing this potential will require rationally designed combination regimens, predictive biomarkers for patient stratification, and a deeper understanding of cell type-specific and context-dependent epigenetic regulation. Only through these advances can the integration of epigenetic modulation with immunotherapy and stroma-targeting approaches ultimately redefine therapeutic strategies for patients with PDAC.
    Keywords:  Epigenetic changes; Epigenetic therapy; Immune cells; Immunotherapy; Pancreatic ductal adenocarcinoma; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13148-026-02081-5
  51. Front Transplant. 2026 ;5 1776806
    Innovative approaches targeting innate immune cells to promote organ transplant tolerance.
    Chiyoshi Toyama, Angus W Thomson.
      Achieving long-term allograft survival while minimizing systemic immunosuppression (IS) remains a critical unmet need in transplantation. While adaptive immunity has traditionally been the primary focus of IS therapy, innate immune cells-that include neutrophils, monocytes, macrophages, dendritic cells, myeloid-derived suppressor cells, innate lymphoid cells (ILCs), natural killer (NK) cells, and gamma delta (γδ) T cells act as key upstream orchestrators of allograft rejection and tolerance. Recent advances in single-cell RNA sequencing and spatial transcriptomics have unveiled the profound heterogeneity of these cell populations, identifying distinct regulatory subsets and novel inhibitory checkpoints. These high-resolution insights provide the scientific rationale for developing innovative precision therapies that can selectively modulate innate immune reactivity without compromising global immunity. Here, we review innovative strategies to target/amplify these mechanisms, including targeting the myeloid inhibitory checkpoints (e.g., leukocyte immunoglobulin-like receptor B; sialic acid-binding immunoglobulin-like lectin-E) to induce tolerogenic phenotypes. We further discuss the modulation of metabolic reprogramming to prevent "trained immunity" using mammalian target of rapamycin inhibitor (mTORi)-loaded nanoparticles, and the use of CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 gene editing to silence T cell costimulatory signals. We evaluate the adoptive transfer of regulatory myeloid cells, -specifically donor-derived regulatory macrophages and regulatory dendritic cells, and innate lymphoid cells in transplant recipients. Furthermore, the potential of targeting specific NK cell and ILC subsets associated with graft regulation is addressed. Collectively, these emerging approaches aim to reprogram the allograft microenvironment, offering a promising paradigm shift towards establishing transplant tolerance.
    Keywords:  dendritic cells; immunotherapy; innate lymphoid cells; macrophages; monocytes; myeloid cells; myeloid-derived suppressor cells; natural killer cells
    DOI:  https://doi.org/10.3389/frtra.2026.1776806
  52. Cancer Pathog Ther. 2026 May;4(3): 165-173
    Targeting immune checkpoint therapy: The role of manganese in tumor immunotherapy.
    Xingyao Lyu, Bixia Li, Zhijie Lin.
      Cancer immunotherapy has emerged as a promising complement to traditional treatments such as radiotherapy and chemotherapy. Although conventional therapies remain central to cancer management, the potential of immunotherapy is increasingly recognized. Immune checkpoint therapy, a key strategy in tumor immunotherapy, has demonstrated significant efficacy against solid tumors. However, its clinical application is hindered by its limited response rate, necessitating efforts to optimize its effectiveness. Recent studies have highlighted the pivotal role of the cyclic GMP-AMP synthase (cGAS) - stimulator of interferon gene (STING) pathway in immune checkpoint therapy. Manganese (Mn), an essential trace element, regulates the activity of CD8+ T and NK cells by modulating the cGAS-STING pathway. Furthermore, the combination of Mn with anti-programmed cell death protein 1 therapy has demonstrated promising anti-tumor effects. Mn also influences immunogenic cell death (ICD), further augmenting its potential as an adjunct to tumor immunotherapy. Despite a growing body of research on the role of Mn in modulating the cGAS-STING pathway and inducing ICD, comprehensive reviews that synthesize these findings and explore the potential of Mn in enhancing immune checkpoint therapy are still lacking. This review aimed to fill this gap by examining the immune mechanisms by which Mn enhances immune checkpoint therapy and its overall impact on tumor immunotherapy.
    Keywords:  Immunogenic cell death; Immunotherapy; Manganese; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cpt.2025.10.001
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