bims-carter 2025-09-21 papers

bims-carter

Biomed News

on CAR-T Therapies

Issue of 2025–09–21
38 papers selected by
Luca Bolliger, lxBio

Breaking barriers: enhancing CAR-armored T cell therapy for solid tumors through microenvironment remodeling.
Engineering CAR-T cells for solid tumors: bispecific antigen targeting, tumor microenvironment modulation, and toxicity control.
Current status of chimeric antigen receptor T cell therapy and its exhaustion mechanism.
CAR T cell persistence in cancer.
The potential of phytomedicines to optimize CAR-T cell therapy in cancer.
Challenges and breakthroughs: current landscape and future prospects of CAR-T cell therapy clinical trials for solid tumors.
Harnessing mRNA-lipid nanoparticles as innovative therapies for autoimmune diseases.
CAR-T cells in solid tumors: Challenges and breakthroughs.
Targeting BCMA in CIDP: Valuable insights gained through multi-omics immune monitoring.
Targeting CD19 CAR-T With MND Promoter Enhances Tumour Killing.
Next-generation multiplex-edited CAR-NK cells: more edits, more power?
Chimeric antigen receptor T-cell therapy and bispecific antibodies in the treatment of lymphoma for human immunodeficiency virus-infected patients: A systematic review.
Isolator-based point-of-care manufacturing: a practical solution for GMP-compliant cell and extracellular vesicles therapy production.
Recombinant AAV gene transfer: Emerging applications in immune modulation and cancer therapy.
The endogenous T cell landscape is reshaped by CAR-T cell therapy and predicts treatment response in multiple myeloma.
Leveraging innate immune signals in CD8+ T cells to boost antitumor immunity.
Correlation Between Chimeric Antigen Receptor T-Cell Pharmacokinetic Data Measured by Flow Cytometry and Quantitative Polymerase Chain Reaction.
Next-generation T cell immunotherapies engineered with CRISPR base and prime editing: challenges and opportunities.
Innate lymphoid cells in the spotlight: from biomarkers to blueprint for innovative immunotherapy.
What We Know and What We Don't Know About the Function of γδ T Cells.
Exploring novel strategies of oncolytic viruses and gut microbiota to enhance CAR-T cell therapy for colorectal cancer.
Transcriptional control of natural killer cell antitumor activity.
Chimeric antigen receptor T-cell (CAR T-cell) and tumor-infiltrating lymphocytes (TILs) therapies in gastrointestinal malignancies: review of literature for clinical applications.
Natural Killer Cell-Mediated Antitumor Immunity: Molecular Mechanisms and Clinical Applications.
Access to novel cancer medicines in Europe: inequities across countries and their drivers.
The FDA-approved and Manufacturer-approved Prescribing Information: Why the Expectation That the Prescriber Has Read It and Suggestions About How to Do So Efficiently.
The dual role of IL-2 in systemic lupus erythematosus: balancing pro-inflammatory and anti-inflammatory effects.
Effects of CRISPR-Cas9-mediated FOXP3 knockout on CAR T cell potency.
Diagnosis of cancer, autoimmune and infectious diseases and prediction of the therapy effectiveness based on the individual's immunotype.
Rewiring natural killer cells for next-generation cancer therapies.
Rheumatoid Arthritis Therapy Based on B Cells.
Development and qualification of a sensitive method for residual feeder cell detection in NK cell therapy products.
T Cells Dysfunction in Multiple Myeloma.
Skin immune microenvironment in psoriasis: from bench to bedside.
Nanobody therapeutics in autoimmune and immune-mediated inflammatory diseases: experimental insights and translational strategies.
Disparities in Imaging and Management of Multiple Sclerosis: A Review.
Decoding paraneoplastic neuromyelitis optica: a multi-omics investigation of tumor-driven T and B cell dynamics.
Revolutionizing tumor diagnosis and treatment: the promise of DNA nanotechnology.

Front Immunol. 2025 ;16 1638186

Breaking barriers: enhancing CAR-armored T cell therapy for solid tumors through microenvironment remodeling.

Tereza Andreou, Constantina Neophytou, Maria Kalli, Fotios Mpekris, Triantafyllos Stylianopoulos.

  Whilst chimeric antigen receptor (CAR) T cell therapy has emerged as a revolutionary immunotherapeutic approach for hematological malignancies in recent years, several challenges remain to potentiate the efficacy of CAR T cell therapies for solid tumors. Here, we focus on the obstacles posed by the tumor microenvironment that hinder the effective trafficking, infiltration and precise tumor targeting by engineered cells. We discuss how the tumor microenvironment presents a physical barrier that needs to be surpassed for effective cell therapies and ongoing efforts in designing innovative CAR T cell therapies with enhanced tumor-targeting precision, improved stability, and overcoming on-target off-tumor toxicity are presented. We focus on recent advances in clinical and preclinical settings to reprogram the immunosuppressive tumor microenvironment, including stroma and blood vessel normalization strategies that can be leveraged to improve the tumor-homing and tumor-targeting potential of engineered therapeutic cells for immuno-oncology applications. As the endeavors for innovative CAR designs continue, we are entering an exciting era in the field of personalized cell therapies offering renewed hope to patients with hard-to-treat solid tumors.

Keywords:  CAR T cell; cell therapy; extracellular matrix normalization; solid tumors; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1638186
Immunol Res. 2025 Sep 20. 73(1): 135

Engineering CAR-T cells for solid tumors: bispecific antigen targeting, tumor microenvironment modulation, and toxicity control.

Tanvi Premchandani, Mohammad Qutub, Amol Tatode, Milind Umekar, Jayshree Taksande, Ujban Md Hussain, Sameer R Khidkikar.

  Chimeric antigen receptor T (CAR-T) cell therapy has revolutionized the treatment of hematologic malignancies, yet its efficacy in solid tumors remains limited due to antigen heterogeneity, immunosuppressive tumor microenvironments, and therapy-associated toxicities. This review highlights advances across CAR-T generations, emphasizing co-stimulatory domains and cytokine-armed TRUCKs to enhance persistence and function. Viral (lentiviral, gamma-retroviral) and non-viral (CRISPR, transposons, mRNA electroporation) delivery systems are compared for efficiency, safety, and scalability, with CRISPR enabling multiplex edits for improved specificity. Dual-targeting CARs counter antigen heterogeneity, while hypoxia-inducible and SynNotch CARs restrict activity to tumor sites. Chemokine receptor engineering enhances infiltration, and armored CARs secreting IL-12 or checkpoint inhibitors remodel the TME. Nanobody-based CAR-T cells further expand design versatility, offering improved stability, tumor penetration, and reduced immunogenicity compared with single-chain variable fragment constructs. Safety innovations include iCasp9 Suicide switches, dasatinib-controlled activation, and cytokine blockade. Clinical trials of bispecific CAR-Ts show promise, yet challenges Like manufacturing complexity and off-target effects persist. Integrating AI-driven design and Personalized neoantigen targeting may unlock CAR-T 2.0 for solid tumors, pending scalable production and regulatory harmonization.

Keywords:  CAR-T cell therapy; CRISPR/Cas9; Dual-targeting CARs; Hypoxia-inducible CARs; Safety switches; Solid tumors; SynNotch receptors; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12026-025-09687-6
Immunotherapy. 2025 Sep 15. 1-19

Current status of chimeric antigen receptor T cell therapy and its exhaustion mechanism.

Huiwen Zhang, Juwei Gao, Zipeng Zhang, Bo Zhang.

  With the rapid advancements in oncology, immunology, and molecular biology, immunotherapy has emerged as a cornerstone of anti-tumor treatment, complementing traditional modalities such as surgery, radiotherapy, and chemotherapy. Among the many immunotherapy strategies, adoptive cell therapy (ACT) is the most representative one. A key technology within ACT is chimeric antigen receptor (CAR) T-cell therapy, a precision-targeted treatment that leverages genetic engineering to modify T cells, enabling them to express antigen-specific receptors independent of major histocompatibility complex (MHC) restrictions. In recent years, continuous optimization of CAR-T therapy has been leading to remarkable clinical outcomes in oncology. However, its efficacy is significantly compromised by T-cell exhaustion, characterized by reduced proliferative capacity, attenuated anti-tumor activity, and limited persistence. Notably, CAR-T cell exhaustion is primarily driven by repeated tumor antigen stimulation, sustained autonomous activation of CAR constructs, and the immunosuppressive tumor microenvironment (TME), collectively contributing to disease relapse in hematologic malignancies and limited efficacy in solid tumors. Therefore, it is important to elucidate and inhibit the mechanism of CAR-T cell dysfunction to improve its efficacy. Overcoming these challenges will facilitate the development of CAR-T cells with sustained proliferative potential and tumor clearance.

Keywords:  CAR-T cell exhaustion; Chimeric antigen receptor T cells; adoptive cell therapy; cancer immunotherapy; tumor immune microenvironment

DOI:  https://doi.org/10.1080/1750743X.2025.2560798
Trends Cancer. 2025 Sep 18. pii: S2405-8033(25)00225-0. [Epub ahead of print]

CAR T cell persistence in cancer.

Katherine P Mueller, Jeremy M Grenier, Evan W Weber.

  Chimeric antigen receptor T cell (CAR T) therapies are 'living drugs' in which T cells are genetically engineered to recognize and kill cancer cells. A major barrier to progress for CAR T targeting liquid and solid tumors is the poor persistence of these cells in vivo, which limits therapeutic efficacy. In this review, we summarize the field's current understanding of CAR T persistence, including clinical observations, patient correlatives and multiomics approaches, and emerging cell engineering and manufacturing strategies. We also propose a conceptual framework for CAR T persistence to guide interpretation of clinical data and the design of more potent and efficacious CAR T therapeutics.

Keywords:  CAR T; T cell exhaustion; cancer; immunotherapy; persistence

DOI:  https://doi.org/10.1016/j.trecan.2025.08.014
Immunotherapy. 2025 Sep 19. 1-14

The potential of phytomedicines to optimize CAR-T cell therapy in cancer.

Ángela Covo-Vergara, Uxue Díez De Ulzurrun-Ripa, Cristian Smerdou, Mercedes Hernández-Rueda, Delia G Estrada-Palafox, Claudia Ureña, Sandra Hervas-Stubbs, Susana Fiorentino, Maritza R Garcia-Garcia.

  Immunotherapy has revolutionized oncology therapeutics landscape. Chimeric Antigen Receptor T-cell (CAR-T) immunotherapy, a form of adoptive cell therapy (ACT) designed to target and kill cancer cells, has shown remarkable success in the treatment of hematological cancer. However, its efficacy against solid tumors remains limited. Phytomedicines represent promising adjuvants to overcome current limitations in cancer immunotherapy due their active compounds that can regulate immune cell functions, modulate immune checkpoint pathways, and reshape the tumoral microenvironment (TME). Current research investigating the TME-modulating effects of certain phytomedicines supports their potential integration as immunotherapy adjuvants. This review focuses on phytomedicines with demonstrated anticancer and immunomodulatory properties, some of which are currently being tested in clinical trials for cancer patients. Despite this promise, significant hurdles persist in the development of phytomedicines as reliable adjuvants in cancer immunotherapy. Consequently, rigorous and focused research is essential to validate their efficacy and safety in this context.

Keywords:  CAR-T cells; Hibiscus Sabdariffa; Immunotherapy; Petiveria alliacea; Piper nigrum; QYSLS; phytomedicines

DOI:  https://doi.org/10.1080/1750743X.2025.2555166
Front Oncol. 2025 ;15 1652329

Challenges and breakthroughs: current landscape and future prospects of CAR-T cell therapy clinical trials for solid tumors.

Jing Guo, Chunhe Zhou, Hongmei Zhao, Huiyan Li.

  Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated significant efficacy in the treatment of hematological malignancies; however, its application in the solid tumor setting remains challenging. Given that solid tumors account for the vast majority of clinically diagnosed cancers, there is an urgent and significant clinical need to develop effective CAR-T therapy. This review focuses on the latest clinical trials of CAR-T therapy in major solid tumors, including glioma, colorectal, pancreatic, prostate, and lung cancers. It systematically evaluates the results of studies targeting key tumor-associated antigens, such as EGFR, IL13Rα2, GD2, B7-H3, CEA, MSLN, PSCA/PSMA, and ROR1. The results indicate that locally delivered, dual-targeted CAR-T cells and engineered CAR-T cells show potential in reducing antigenic escape and enhancing cellular function. Significant survival benefit and tumor remission were observed in some studies. However, antigen heterogeneity-driven escape, tumor immunosuppressive microenvironment, insufficient persistence of CAR-T cells in vivo, and treatment-related toxicity still limit their efficacy and clinical application. To address these challenges, we further discuss various optimization strategies, including target selection, combination of immune checkpoint inhibitors or tumor microenvironment modulators, and optimization of CAR structural design and delivery methods. In the future, through the exploration of multi-dimensional optimization design and combination therapeutic regimen, it is expected to facilitate the broader application and clinical translation of CAR-T therapy in solid tumor treatment.

Keywords:  CAR-T cell therapy; antigen escape; clinical trials; solid tumors; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2025.1652329
Mol Ther Methods Clin Dev. 2025 Sep 11. 33(3): 101566

Harnessing mRNA-lipid nanoparticles as innovative therapies for autoimmune diseases.

Rose Razavi, Michael Kegel, Jenna Muscat-Rivera, Drew Weissman, Jilian R Melamed.

  Autoimmune diseases are chronic conditions where the immune system mistakenly attacks healthy tissues, leading to potentially debilitating symptoms that require lifelong management. There are no cures for autoimmune diseases, and new treatments are urgently needed to improve patient outcomes. This review delves into the compelling advancements and ongoing challenges in harnessing mRNA-lipid nanoparticles (LNPs) as innovative therapies for autoimmune diseases. mRNA-LNPs enable a range of therapeutic approaches to combat autoimmune diseases, including targeted immune cell modulation, tissue regeneration, antigen-specific tolerizing immunotherapy, and in vivo chimeric antigen T cell therapies. To successfully advance this promising class of therapies to the clinic, key challenges must be addressed, such as mitigating unwanted inflammation caused by LNPs, overcoming biological barriers to delivery, and ensuring the long-term safety of mRNA-LNPs specifically in autoimmune contexts. Through their modular design, flexible application, and potential for cost-effective production, mRNA-LNP therapies offer exciting clinical potential to transform the management of autoimmune diseases.

Keywords:  CAR T cell therapy; autoimmune diseases; lipid nanoparticles; mRNA therapeutics; targeted drug delivery; tolerizing vaccines

DOI:  https://doi.org/10.1016/j.omtm.2025.101566
Cell Rep Med. 2025 Sep 12. pii: S2666-3791(25)00426-4. [Epub ahead of print] 102353

CAR-T cells in solid tumors: Challenges and breakthroughs.

Giulia Escobar, Trisha R Berger, Marcela V Maus.

  Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies, but its efficacy in solid tumors is limited by several challenges. Key obstacles include insufficient CAR-T cell trafficking to tumors, limited expansion and persistence, tumor relapse due to antigen loss or heterogeneity, and an immunosuppressive tumor microenvironment (TME) that dampens CAR-T cell functions. In this review, we discuss insights from recent successful clinical trials in advanced solid tumors and highlight groundbreaking strategies integrating synthetic biology and gene engineering to enhance CAR-T cell fitness, potency, and persistence, activate host immunity, reprogram the TME, and enable multi-antigen targeting. We examine strengths and weaknesses of current preclinical models for assessing the efficacy and safety of CAR-T cell therapies, including human xenografts in immunodeficient mice and humanized or syngeneic models. The array of cutting-edge approaches employed in next-generation CAR-T cell therapies is expected to transform the treatment landscape of solid tumors.

Keywords:  CAR-T cells; CRISPR-screens; armored CAR-T cells; solid tumors; tumor microenvironment

DOI:  https://doi.org/10.1016/j.xcrm.2025.102353
Med. 2025 Sep 12. pii: S2666-6340(25)00180-1. [Epub ahead of print]6(9): 100753

Targeting BCMA in CIDP: Valuable insights gained through multi-omics immune monitoring.

Maximilian A Funk, Sebastian Theurich.

Dong et al. present two patients with refractory chronic inflammatory demyelinating polyneuropathy (CIDP), who received treatment with B-cell-maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T cells.1 Extensive concomitant immune monitoring provides insights into the pathogenesis and mechanisms of relapse in CIDP that may help to determine the role of BCMA-targeted CAR-T cell therapy for this disease in the future.

DOI: https://doi.org/10.1016/j.medj.2025.100753
J Cell Mol Med. 2025 Sep;29(18): e70843

Targeting CD19 CAR-T With MND Promoter Enhances Tumour Killing.

Xiaomei Zhang, Xiaoyuan He, Yu Zhang, Jile Liu, Shujing Guo, Cuicui Lyu, Mingfeng Zhao.

  Although Chimeric antigen receptor (CAR) T cell therapy has demonstrated a high remission rate in B cell acute lymphoblastic leukaemia, concerns regarding toxicity and disease recurrence remain. Different promoters can modulate the expression levels of CAR molecules on the cell surface. In this study, we systematically compared four distinct promoters (MND, MSCV, EF-1α and CMV). Our findings revealed that while these promoters exhibited similar characteristics, the MND promoter demonstrated superior viral packaging and transduction efficiency. Furthermore, it enhanced the anti-leukaemia efficacy by increasing the proportion of naïve T cells involved in the cytotoxic process.

Keywords:  B‐ALL; CAR‐T; CD19; MND; promoter

DOI:  https://doi.org/10.1111/jcmm.70843
J Immunother Cancer. 2025 Sep 15. pii: e012841. [Epub ahead of print]13(9):

Next-generation multiplex-edited CAR-NK cells: more edits, more power?

Tobias Bexte, Dimitrios L Wagner.

  First clinical trials demonstrated the safety of adoptive cell transfer with allogeneic natural killer (NK) cell products from healthy donors, making them an attractive candidate for 'off-the-shelf' chimeric antigen receptor (CAR)-immune cell therapy. However, reduced persistence and inactivation of NK cells by immunosuppressive cues likely limit the performance of CAR-redirected NK cells. Wang and colleagues demonstrate that multiplex CRISPR base editing allows optimization of the intrinsic functionality of CAR-NK cells improving their therapeutic potential. In contrast to conventional CRISPR-Cas nucleases, base editing avoided most double-stranded DNA breaks while enabling highly efficient editing at up to six sites simultaneously. The study further demonstrates the feasibility of a non-viral approach to integrate CAR transgene and multiplex base editing of several immune checkpoints in NK cells using a single electroporation. CAR-NK cells harboring up to three base edits demonstrate improved potency over unedited counterparts in vitro. Xenograft mouse models confirmed increased potency, but also indicated signs of organ toxicity - a phenomenon that will require future studies prior to clinical translation. The study demonstrates that CRISPR base editing is a powerful tool to unleash the full cytotoxic potential of NK cells, but it also warrants the question: How many internal breaks can be removed without hurting CAR-NK cell therapy's impeccable safety record?

Keywords:  Adoptive cell therapy - ACT; Chimeric antigen receptor - CAR; Immune Checkpoint Inhibitor; Immunotherapy; Natural killer - NK

DOI:  https://doi.org/10.1136/jitc-2025-012841
SAGE Open Med. 2025 ;13 20503121251374954

Chimeric antigen receptor T-cell therapy and bispecific antibodies in the treatment of lymphoma for human immunodeficiency virus-infected patients: A systematic review.

Alejandra Viera Plasencia, Jeremy I Purow, Julia Steger, Alexander Brown-Whalen, Henna Qadri, Nicolas Duque Clavijo, Marco Ruiz-Andia.

   Background: Chimeric antigen receptor T-cell therapy has emerged as a highly effective treatment for relapsed and refractory lymphomas; however, its application in individuals with human immunodeficiency virus remains underexplored. People with human immunodeficiency virus face an increased risk of developing malignancies such as lymphoma, where standard chemotherapy often results in suboptimal responses and heightened toxicity.
Objective: To review and synthesize current literature on the use of chimeric antigen receptor T-cell therapy and bispecific antibodies in human immunodeficiency virus-associated lymphoma, examining efficacy, safety, and potential barriers to implementation.
Methods: A systematic review of the literature was conducted using PubMed. Included studies comprised clinical trials, cohort studies, case reports, and preclinical research published between January 2000 and September 2024. Search terms included "HIV," "lymphoma," "CAR T cell therapy," "bispecific antibodies," "immunotherapy," and "HIV-associated lymphoma."
Results: Preliminary data suggest chimeric antigen receptor T-cell therapy is feasible in human immunodeficiency virus-positive patients, with response rates comparable to human immunodeficiency virus-negative populations and manageable adverse events, including cytokine release syndrome and neurotoxicity. Engineering chimeric antigen receptor T cells to target human immunodeficiency virus-infected cells is under investigation as a potential curative strategy. However, challenges such as immunosuppression, low antigen expression, and interactions with antiretroviral therapy complicate treatment. Bispecific antibodies have shown promise in hematologic malignancies, but data in people with human immunodeficiency virus remain limited due to trial exclusions.
Conclusion: Early findings support the feasibility and potential efficacy of chimeric antigen receptor T-cell therapy in human immunodeficiency virus-associated lymphoma. Larger, controlled trials are needed to establish safety, optimize treatment strategies, and expand therapeutic options for people with human immunodeficiency virus.

Keywords:  ART interactions; CAR T therapy; HIV immunotherapy; HIV lymphoma; bispecific antibodies

DOI:  https://doi.org/10.1177/20503121251374954
Front Bioeng Biotechnol. 2025 ;13 1644318

Isolator-based point-of-care manufacturing: a practical solution for GMP-compliant cell and extracellular vesicles therapy production.

Yu-Sung Chiu, Kun-Liang Wang, Kun-Lieh Wu.

  Cell and extracellular vesicle (EV)-based therapies represent a promising frontier in regenerative medicine and immunotherapy. However, their clinical translation is often constrained by the complexities of Good Manufacturing Practice (GMP)-compliant production, particularly under centralized manufacturing models. This Perspective discusses the emerging role of decentralized, point-of-care (POC) manufacturing in enabling timely, scalable, and patient-specific delivery of cell and EV therapeutics, with a focus on isolator-based systems as core manufacturing infrastructure. We discuss current advances in closed-system technologies, regulatory frameworks, and quality control (QC) strategies supporting GMP compliance in decentralized environments. Real-world applications and case studies illustrate feasibility and translational impact. Isolator-based platforms offer modular, sterile, automation-compatible environments that support both autologous and selected allogeneic product manufacturing at clinical sites. These systems reduce contamination risks, lower facility requirements, and enable integration with real-time QC testing. Despite these advantages, challenges remain, including regulatory ambiguity, workforce training limitations, and quality assurance gaps in decentralized settings. Emerging solutions include automated closed-system bioreactors, digitalized QC workflows, and harmonized operational standards to ensure product safety and consistency. Strategic coordination among regulators, hospitals, and developers will be essential to overcome operational and compliance hurdles. With appropriate infrastructure, skilled personnel, and standardized processes in place, isolator-based POC manufacturing holds the potential to transform how advanced therapies are produced and delivered-ultimately enhancing patient access to safe, effective, and personalized cell and EV-based treatments.

Keywords:  GMP-good manufacturing practice; cell therapy; extracellular vesicles (EVs); isolator; point-of-care manufacturing

DOI:  https://doi.org/10.3389/fbioe.2025.1644318
Biochem Pharmacol. 2025 Sep 12. pii: S0006-2952(25)00597-0. [Epub ahead of print]242(Pt 2): 117332

Recombinant AAV gene transfer: Emerging applications in immune modulation and cancer therapy.

Yixuan Yang, Rongtao Chen, Yuchen Bao, Heqiao Han, Kai Ma, Xiaolei Pei, Lei Zhang, Wenwei Shao.

  Advancements have been achieved in gene transfer using recombinant adeno-associated virus (rAAV). rAAVs with distinct tissue tropisms are used to deliver target genes safely and accurately to specific host tissue. Although primarily used for treating monogenic disease, rAAV vectors also have potential in the field of immune modulation. Gene delivery through rAAV vectors, particularly those encoding immune regulatory molecules, not only mitigates inflammation and corrects immune dysfunction but also suppresses tumor growth and enhances the efficacy of Chimeric Antigen Receptor T cell therapy via immune modulation, thereby exerting anti-cancer effects. rAAV-based immune therapies primarily focus on autoimmune diseases, including rheumatoid arthritis, autoimmune uveitis, multiple sclerosis and other genetic immune diseases but may also be used to treat hepatocellular carcinoma, glioma and ovarian cancer. The present review aims to outline the advantages and limitations of rAAV gene delivery vectors and their potential applications in immune therapy.

Keywords:  Autoimmune disease; Cancer therapy; Gene delivery; Immune modulation; Recombinant adeno-associated virus

DOI:  https://doi.org/10.1016/j.bcp.2025.117332
Leukemia. 2025 Sep 19.

The endogenous T cell landscape is reshaped by CAR-T cell therapy and predicts treatment response in multiple myeloma.

Julia Frede, Julia C Poller, Kayleen Shi, Hannah Stuart, Noori Sotudeh, Claire Havig, Klothilda Lim, Caroline R M Wiggers, Eugene Y Cho, Tushara Vijaykumar, Jianlin Liu, Johannes M Waldschmidt, Monica S Nair, Praveen Anand, Valeriya Dimitrova, Anna Montanaro, Andrew J Yee, Nikhil C Munshi, Kenneth C Anderson, Nathan Martin, Shari M Kaiser, Marc-Steffen Raab, Noopur S Raje, Birgit Knoechel, Jens G Lohr.

While most patients initially respond to CAR-T cell treatment, responses often are not durable and subsequent lines of immunotherapy show diminishing success. In this study, we investigated the co-evolutionary dynamics between CAR-T cells and the immune microenvironment in myeloma patients undergoing anti-BCMA CAR-T cell therapy at single-cell resolution. Our findings highlight the transformative impact of CAR-T cell treatment on the endogenous T cell landscape. We identify a novel transitional CD8 + T cell population that is predictive of poor treatment outcomes. The emergence of this population coincides with the depletion of the endogenous T cell repertoire and compositional evolution of functional T cell subsets. These changes in the endogenous T cell compartment induced by CAR-T cell therapy may contribute to inadequate immune capacity and tumor control. Our findings highlight the potential of targeting TIM3/GAL9 interactions to mitigate T cell exhaustion, apoptosis and lack of persistence, offering promising avenues for optimizing T cell-based cancer immunotherapies. We provide a framework for assessing and manipulating the 'mileage' of the immune system as predictive marker and therapeutic opportunity to prevent repeated immunotherapies from becoming increasingly less successful, even when targeting distinct antigens.

DOI: https://doi.org/10.1038/s41375-025-02766-5
Front Immunol. 2025 ;16 1617773

Leveraging innate immune signals in CD8+ T cells to boost antitumor immunity.

Gabriella K Albert, Phoebe Cao, Eduardo Davila.

  Pattern recognition receptors (PRRs), traditionally characterized in innate immune cells, are emerging as critical modulators of T cell function. Toll-like receptors (TLRs), STING, RIG-I-like receptors (RLRs), and natural killer receptors (NKRs) are expressed by CD8+ T cells, where they influence various cellular responses. Primarily serving as noncanonical costimulatory signals, TLRs can modulate T cell activation, differentiation, metabolic fitness, and memory formation. RLRs and STING can promote T cell expansion and cytokine production. Both activating and inhibitory NKRs can also alter T cell cytotoxicity and differentiation. As demonstrated in recent advancements, the capacity of these signaling cascades to enhance T cell responses offers promising therapeutic opportunities in cancer. Clinical strategies are being developed to selectively harness each of these pathways, such as TLR and STING agonists to bolster antitumor responses, and NKR-based approaches to amplify cytotoxic function. Additionally, adoptive T cell therapies, such as chimeric antigen receptor (CAR)-T cells, are incorporating these innate signaling components to overcome tumor-mediated immunosuppression, enhance functional longevity, and improve therapeutic efficacy. This review discusses the progress made to characterize the role of T cell intrinsic PRR activity in shaping T cell functions and highlights recent advancements in that leverage innate receptor signaling to enhance the efficacy of cancer immunotherapies.

Keywords:  T cell immunotherapy; antitumor immunity; innate receptor signaling; innate-like stimulation; pattern recognition receptors

DOI:  https://doi.org/10.3389/fimmu.2025.1617773
Clin Transl Sci. 2025 Sep;18(9): e70354

Correlation Between Chimeric Antigen Receptor T-Cell Pharmacokinetic Data Measured by Flow Cytometry and Quantitative Polymerase Chain Reaction.

Wenjie Wang, Xiaojia Liu, Tairan Yang, Jing Wang, Jin Liu, Yuqing Wang, Jie Yu, Tracy Luo, Xiaodi Wang, Jian Li, Chuan Wang, Ning Chen, Dong Geng, Da Xu.

  Chimeric antigen receptor (CAR)-T cells have antitumor efficacy in hematological and solid malignancies. Unlike small molecules or antibodies, CAR-T cells have unique kinetic profiles (distribution, expansion, contraction, and persistence). To quantify these dynamics, flow cytometry and qPCR are commonly used, each with distinct advantages and limitations. We analyzed the correlation between flow cytometry and qPCR quantification of CAR-T cells in subjects from 4 phase 1 clinical studies (individually and combined). We also explored factors that affect calculations of CAR-T cells and CAR transgene copy number, how these affect pharmacokinetic (PK) parameters determination for clinical studies, and associations with pharmacodynamic factors such as cytokine levels. We demonstrate that CAR transgene copy number is more highly correlated with the ratio of CAR-T cells to white blood cells (WBCs) than with the actual number of CAR-T cells, indicating that CAR transgene copy number is related to the percentage of CAR-T cells in blood. The low level of correlation between CAR transgene copy number and CAR-T cells may be due to differences in the ratio of CAR-T cells to WBCs at some time points. Meanwhile, flow cytometry and qPCR PK values correlated with cytokine levels; flow cytometry data had a higher correlation coefficient (r) and lower p-values than qPCR data. These findings increase our understanding of potential causes of inconsistencies in PK and pharmacodynamic parameters analyzed during studies of CAR-T cell therapy.

Keywords:  T‐cell expansion; T‐cell receptor; anti‐tumor immune response; biomarkers

DOI:  https://doi.org/10.1111/cts.70354
Nat Rev Clin Oncol. 2025 Sep 19.

Next-generation T cell immunotherapies engineered with CRISPR base and prime editing: challenges and opportunities.

Karl Petri, Elvira D'Ippolito, Annette Künkele, Ulrike Köhl, Dirk H Busch, Hermann Einsele, Michael Hudecek.

T cells can be reprogrammed with transgenic antigen recognition receptors, including chimeric antigen receptors and T cell receptors, to selectively recognize and kill cancer cells. Such adoptive T cell therapies are effective in patients with certain haematological cancers but challenges persist, including primary and secondary resistance, a lack of efficacy in patients with solid tumours, a narrow range of targetable antigens, and time-consuming and complex manufacturing processes. CRISPR-based genome editing is a potent strategy to enhance cellular immunotherapies. Conventional CRISPR-Cas9 systems are useful for gene editing, transgene knock-in or gene knockout but can result in undesired editing outcomes, including translocations and chromosomal truncations. Base editing and prime editing technologies constitute a new generation of CRISPR platforms and enable highly precise and programmable installation of defined nucleotide variants in primary T cells. Owing to their high precision and versatility, base editing and prime editing systems, hereafter collectively referred to as CRISPR 2.0, are advancing to become the new standard for precision-engineering of cellular immunotherapies. CRISPR 2.0 can be used to augment immune cell function, broaden the spectrum of targetable antigens and facilitate streamlined production of T cell therapies. Notably, CRISPR 2.0 is reaching clinical maturity, with multiple clinical trials of CRISPR 2.0-modified cellular therapies currently ongoing. In this Review, we discuss emerging CRISPR 2.0 technologies and their progress towards clinical translation, highlighting challenges and opportunities, and describe strategies for the use of CRISPR 2.0 to advance cellular immunotherapy for haematological malignancies and solid tumours in the future.

DOI: https://doi.org/10.1038/s41571-025-01072-4
Front Immunol. 2025 ;16 1655730

Innate lymphoid cells in the spotlight: from biomarkers to blueprint for innovative immunotherapy.

I-Chih Kuo, Julyanne Brassard, Peter W Zandstra, Kelly M McNagny.

  Since their discovery, innate lymphoid cells (ILCs) have emerged as key players in immune regulation, tissue homeostasis, and disease pathogenesis. Early research focused on defining ILC subsets, including ILC1s, ILC2s, ILC3s, and lymphoid tissue inducer (LTi) cells, by distinguishing their development, transcriptional profiles, and effector functions relative to T cells. Subsequent studies characterized the tissue-resident nature of ILCs and mapped their context-dependent phenotypes across diverse organs. In parallel, increasing evidence linked ILC subset imbalances to the pathogenesis of autoimmune diseases and various cancers. Recent work has leveraged circulating ILC frequencies and phenotypes as potential biomarkers for disease severity and progression. Notably, the immunomodulatory, tissue-reparative, and cytotoxic functions of helper ILCs have attracted interest as novel therapeutic avenues. Current strategies to harness ILCs for therapy include ex vivo expansion of autologous or allogeneic ILCs, derivation of ILC-like cells from umbilical cord blood or pluripotent stem cells (PSCs), and engineering of ILCs with chimeric antigen receptors (CARs) to enhance antigen specificity. Additionally, cytokine modulation and immune checkpoint blockade are being explored to sustain or redirect ILC function in disease contexts. This review synthesizes recent advances in understanding the functional diversity, plasticity, and tissue residency of ILC subsets, emphasizing their interactions with other immune and stromal cells, and their roles as predictive, diagnostic, and therapeutic targets in autoimmune diseases and cancers. Key translational challenges, including subset heterogeneity, plasticity, tissue-restricted residency, and limited scalability, remain barriers to clinical application. However, emerging multi-omic technologies, single-cell atlases, and synthetic biology approaches are accelerating efforts to map ILC states with unprecedented resolution and guide rational therapeutic design. Looking forward, integration of ILC-based therapies with regenerative medicine, cellular engineering, and immuno-oncology platforms holds promise for developing next-generation precision immunotherapies. By bridging fundamental biology with translational innovation, this field is poised to expand the therapeutic landscape for both autoimmune and malignant diseases.

Keywords:  autoimmune diseases; biomarkers; cancer; chronic inflammatory diseases; immunotherapy; innate lymphoid cells (ILCs); regenerative medicine

DOI:  https://doi.org/10.3389/fimmu.2025.1655730
Eur J Immunol. 2025 Sep;55(9): e70058

What We Know and What We Don't Know About the Function of γδ T Cells.

Immo Prinz, Anja Meyer.

  γδ T cells, long regarded as unconventional relatives of αβ T cells, have emerged as pivotal players in immunity, with unique biology and therapeutic promise. Recent advances in single-cell multiomics, refined mouse models, and human cohort studies have deepened insights into their TCR-ligand interactions, developmental pathways, and context-dependent functions. This mini-review synthesizes current understanding from structural studies of γδ TCR recognition and developmental regulation-including inborn errors of immunity-to adaptive-like clonal expansions shaped by infection, aging, and environmental cues. It also highlights their dual roles in cancer, where subsets can exert potent cytotoxicity or promote tumor progression, and discusses strategies to optimize their antitumor potential through checkpoint blockade, metabolic modulation, and engineered receptors. Beyond immunity to malignancy, γδ T cells contribute to tissue homeostasis, repair, and regulation of inflammatory processes in diverse organs, influencing outcomes in neuroinflammation, autoimmunity, and fibrotic diseases. Together, these perspectives form the foundation of a special issue in the European Journal of Immunology (https://onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1521-4141.T-cells) dedicated to advancing the understanding of γδ T cell biology and clinical potential.

Keywords:  T cells; γδ T cell function; γδ T cells; γδ TCR; γδ TCR ligands

DOI:  https://doi.org/10.1002/eji.70058
Cell Immunol. 2025 Sep 13. pii: S0008-8749(25)00112-1. [Epub ahead of print]417 105026

Exploring novel strategies of oncolytic viruses and gut microbiota to enhance CAR-T cell therapy for colorectal cancer.

Jia Yi, Sangmu Quji, Luxuan Guo, Zhongqiu Chai, Xianbin Kong, Jingyan Meng.

  Colorectal cancer (CRC), ranking as the third most prevalent malignant tumor globally (accounting for 10.0 % of new cancer cases) and the second leading cause of cancer-related deaths (9.4 % of cancer mortality), continues to escalate in incidence, posing a significant threat to human health. Although conventional therapies such as surgery, radiotherapy, and chemotherapy remain the clinical mainstay, their efficacy in improving patient survival and quality of life has reached a plateau, necessitating the exploration of novel therapeutic approaches. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a highly promising approach for cancer treatment. Notably, the complexity of the solid tumor microenvironment (TME) presents challenges for the application of CAR-T therapy in CRC, including antigen heterogeneity, immune suppression, and off-target toxicity. However, the development of multi-target CAR-T cells and their combination with immunomodulatory drugs holds significant clinical potential. Furthermore, in recent years, oncolytic virus (OV) therapy has garnered substantial attention due to its unique antitumor mechanisms. Our study demonstrates that OVs can precisely target CRC tissues, inducing tumor cell apoptosis through selective infection and intracellular replication while concurrently activating systemic antitumor immune responses and inhibiting angiogenesis, thereby achieving multidimensional therapeutic effects. Further investigations reveal that OVs can serve as gene delivery vectors for therapeutic molecules or synergize with chimeric antigen receptor T-cell (CAR-T) therapy and immune checkpoint inhibitors to significantly enhance treatment efficacy. Simultaneously, gut microbiota, a critical regulator of CRC progression, can influence both CAR-T and OVs therapies through metabolic modulation and immune remodeling. Building upon these mechanisms, this review innovatively proposes a tripartite "OVs-gut microbiota-CAR-T" strategy: OVs may reprogram the immunosuppressive TME and release tumor antigens to enhance CAR-T infiltration and activity, while concurrent modulation of gut microbiota could further alleviate immunosuppression and reduce treatment toxicity, establishing a bidirectional synergistic loop. This interdisciplinary integration strategy may provide a groundbreaking approach to overcome current therapeutic limitations in CRC and advance precision tumor immunotherapy to new frontiers.

Keywords:  CAR-T; Colorectal cancer; Combination therapy; Gut microbiota; Oncolytic virus

DOI:  https://doi.org/10.1016/j.cellimm.2025.105026
Trends Immunol. 2025 Sep 18. pii: S1471-4906(25)00217-0. [Epub ahead of print]

Transcriptional control of natural killer cell antitumor activity.

Barbara L Kee.

  Natural killer (NK) cells protect from viral infection, cancer, and metastasis, and are emerging as valuable therapeutics for cancer treatment. NK-cell control of viral infection has been studied intensively, but less is known in the context of cancer. Multiple associative, preclinical, and early phase clinical studies have revealed the ability of NK-cell-based therapies to contribute to cancer control. Development of effective NK-cell therapeutics will be facilitated by a deeper understanding of the mechanisms controlling NK cell function across an array of cancer types and states. This review will focus on recent studies of the transcription factors that control NK cell function and their response to leukemia, solid tumors, and metastasis.

Keywords:  immunotherapy; natural killer cell; transcription factor

DOI:  https://doi.org/10.1016/j.it.2025.08.007
Med Oncol. 2025 Sep 20. 42(11): 481

Chimeric antigen receptor T-cell (CAR T-cell) and tumor-infiltrating lymphocytes (TILs) therapies in gastrointestinal malignancies: review of literature for clinical applications.

Mohamed Saad Sayed, Ahmed Farid Gadelmawla, Osama Abouelenin, Elsayed S Moubarak, Nada S Jibril, Mahmoud Kandeel, Hebatullah Abdulazeem.

  Gastrointestinal malignancies (GI malignancies) have had a notoriously dismal prognosis throughout history. The primary therapeutic approaches to treat and manage GI malignancies are immunotherapy, radiotherapy, surgery, and chemotherapy, which may include monotherapy or a combination of these therapies to boost the effect. Nevertheless, the recurrence and metastasis rates remain elevated. In recent decades, immunotherapies have had a powerful impact when included in treatment regimens. In hematologic malignancy, chimeric antigen receptor T cells (CAR-T cell) have shown a promising anticancer impact as one of the immunotherapies. It gives a promising treatment option for solid tumors, including colorectal cancers. In recent clinical trials, the CAR-T cells showed a promising effect on pancreatic, colorectal, esophageal, hepatocellular, and gastric cancers. Tumor-infiltrating lymphocyte (TIL) therapy is another immunotherapy option with promising option for GI malignancies. Through the process of designing the TIL therapy, T cells are extracted and designed according to the nature of the GI malignancy. In this review, we addressed the clinical applications of both therapies while highlighting the challenges and possible strategies to overcome them. CAR T-cells and TIL therapies showed good responses with tolerable and acceptable side effects in treating GI malignancies such as pancreatic, colorectal, gastric, and hepatocellular cancers, while the immunosuppressive tumor microenvironment (TME) inhibiting the activity of immunotherapy and impeding its efficacy is a significant challenge.

Keywords:  CAR T-cells; Chimeric antigen receptor T cells; GI malignancies; Gastrointestinal malignancies; TIL therapy; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1007/s12032-025-03040-5
MedComm (2020). 2025 Sep;6(9): e70387

Natural Killer Cell-Mediated Antitumor Immunity: Molecular Mechanisms and Clinical Applications.

Nanzhi Luo, Cong Chen, Wenjing Zhou, Jianqi Hao, Song He, Yu Liu, Yin Ku, Linhua Huang, Chuanfen Zhang, Yueli Shu, Xiaoqing Wu, Yaojia Zhou, Jian Zhang.

  Natural killer (NK) cells are pivotal effectors in innate antitumor immunity by mediating cytotoxicity, secreting cytokines, or expressing cell membrane receptors, which facilitate interactions with other immune cells. The cytotoxic activity and immune function of NK cells are governed by dynamic receptor-ligand interactions, cytokine networks, and metabolic-epigenetic crosstalk within the tumor microenvironment (TME). Recent years, NK cell-based therapies are emerging as a promising clinical approach for antitumor treatment, owing to their rapid response, unique recognition mechanisms, potent cytotoxic capabilities, and memory-like characteristics, along with their low risk of posttreatment adverse effects and cost effectiveness. However, immunosuppression and metabolic reprogramming driven by TME subvert NK cell surveillance, impairing its antitumor function. This review comprehensively details molecular mechanisms underpinning NK cell dysfunction, including dysregulated activating/inhibitory receptor signaling, metabolic reprogramming, and epigenetic silencing of effector genes. We further synthesize advances in clinical strategies to restore NK cytotoxicity including ex vivo expansion for adoptive transfer, chimeric antigen receptor-NK engineering, TME-remodeling agents, immune checkpoint blockade, cytokine-based therapies, and NK cell engagers targeting tumor antigens. By bridging mechanistic insights with translational applications, this work provides a framework for rationally designed NK cell-based immunotherapies to overcome resistance across solid and hematologic malignancies.

Keywords:  NK cells; TME; clinical strategies; metabolic reprogramming; molecular crosstalk

DOI:  https://doi.org/10.1002/mco2.70387
ESMO Open. 2025 Sep 17. pii: S2059-7029(25)01679-5. [Epub ahead of print]10(10): 105810

Access to novel cancer medicines in Europe: inequities across countries and their drivers.

T Hofmarcher, A Charalambous, N Normanno, E Szmytke, N Wilking.

   BACKGROUND: An increasing number of cancer medicines are being developed and approved. Access to these medicines is important for improving patient outcomes and overall quality of care, yet achieving equitable access across countries in Europe is challenging.
METHOD: This study reviews inequities in access to novel cancer medicines in countries of the European Union (EU) and European Economic Area (EEA), and neighboring countries, at three critical stages: regulatory approval, reimbursement approval, and use in clinical practice. It also examines reasons contributing to these inequities. The analysis builds on published evidence from a predefined set of international stakeholders.
RESULTS: Inequities vary across the three stages. At the regulatory stage, disparities are minimized within EU/EEA countries due to centralized approval by the European Medicines Agency (EMA), while worse access exists outside this region. Reimbursement of EMA-approved medicines varies significantly, with rates ranging from 0% in Malta to 96% in Germany, and timelines spanning <100 days to nearly 1000 days. Alternative access schemes enable (limited) access before and after regulatory and reimbursement approval, which may change conclusions about access in some countries. Clinical use exhibits a 10-fold difference across countries in some cases, with Central and Eastern Europe consistently lagging. Contributing factors include country-specific prioritization of pharmaceutical companies for regulatory and reimbursement applications, health technology assessment (HTA) processes and criteria, constraints in financial resources for medicines and testing infrastructure, suboptimal care processes, organization, and continuing medical education.
CONCLUSION: Patient access to novel medicines differs widely across European countries, caused by financial, organizational, administrative, and capacity reasons. Policy harmonization, as seen with mandatory regulatory approval by the EMA and the EU HTA Regulation, has the potential to reduce inequities, but it will not address underlying economic and health care system constraints. Achieving equity will require a balance between innovation, affordability, and sustainability in health care systems.

Keywords:  Europe; cancer medicines; drug access; inequity; reimbursement decision

DOI:  https://doi.org/10.1016/j.esmoop.2025.105810
J Psychiatr Pract. 2025 Sep 01. 31(5): 267-269

The FDA-approved and Manufacturer-approved Prescribing Information: Why the Expectation That the Prescriber Has Read It and Suggestions About How to Do So Efficiently.

Sheldon H Preskorn.

  Based on survey feedback, ~5% of prescribers do not understand the importance of the prescribing information (PI) provided by the U.S. Food and Drug Administration (FDA) and the specific manufacturer of the drug, even though it is provided every time the drug is dispensed. This column addresses 3 representative comments from this subset of prescribers about whether it is an appropriate expectation that the prescriber be familiar with the PI, whether by reading it in its entirety or the first page summary and any additional sections that they wish to know. It also discusses that many, if not all, prescribing "guides" are in fact the PI reformatted for the guide. This column refers the reader back to earlier columns that discuss some of these matters in more detail. This column also addresses comments by 8% of surveyed prescribers about the need for training programs to cover this information for the benefit of prescribers in training and their eventual patients.

Keywords:  U.S. Food and Drug Administration (FDA); drug approval process; efficient reading; medical malpractice; package insert; prescribing information (PI); product label

DOI:  https://doi.org/10.1097/PRA.0000000000000885
Cytokine. 2025 Sep 18. pii: S1043-4666(25)00179-6. [Epub ahead of print]196 157032

The dual role of IL-2 in systemic lupus erythematosus: balancing pro-inflammatory and anti-inflammatory effects.

Hao Li, Xiang Lin, Jing He.

  Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by chronic inflammation and immune dysregulation. Interleukin-2 (IL-2), a central cytokine in T-cell biology, plays a paradoxical role in SLE pathogenesis. On one hand, it promotes effector T cell and natural killer (NK) cell activity, thereby amplifying inflammation; on the other, it supports the expansion and function of regulatory T cells (Tregs), which are essential for maintaining immune tolerance. This dual functionality makes IL-2 a driver of autoimmunity and a potential immunotherapeutic target. This review outlines the molecular mechanisms underlying IL-2's pro- and anti-inflammatory roles in SLE, highlights the regulatory factors that shape its functional balance, such as receptor affinity, dosing, exposure duration, and the immune microenvironment, and discusses recent progress in low-dose IL-2therapy and engineered IL-2 variants. A comprehensive understanding of IL-2 signaling dynamics is essential for the designing development of precision therapies designed to restore immune homeostasis in SLE.

Keywords:  Interleukin-2 (IL-2); Regulatory T cell (Treg); Systemic lupus erythematosus (SLE)

DOI:  https://doi.org/10.1016/j.cyto.2025.157032
Mol Ther Methods Clin Dev. 2025 Sep 11. 33(3): 101570

Effects of CRISPR-Cas9-mediated FOXP3 knockout on CAR T cell potency.

Lena Peter, Martí Farrera-Sal, Ferhat Ali Yaman, Nils Henrik Dempewolf, Samira Picht, Sarah Schulenberg, Jonas Kath, Frederik Hamm, Frederik Heinrich, Dimitrios L Wagner, Mir-Farzin Mashreghi, Annette Künkele, Petra Reinke, Julia K Polánsky, Michael Schmueck-Henneresse.

  Persistent antigen stimulation and inflammatory environments drive exhaustion, senescence, and activation-induced cell death, impairing both endogenous and therapeutic T cells. Understanding the mechanisms underlying T cell dysfunction is critical for improving immunotherapies. While the transcription factor forkhead box protein P3 (FOXP3) is primarily known for its role in regulatory T cell development and maintenance, recent studies suggest it may also influence effector T cell function. However, its impact on therapeutic T cells, including CAR T cells, remains poorly defined. Here, we used non-viral CRISPR-Cas9 editing to knockout FOXP3 in CD19-directed CAR T cell products (TCPs) generated via lentiviral transduction. FOXP3 expression was upregulated at both the protein and RNA level following CAR stimulation. Compared to unmodified CAR TCPs, FOXP3-KO CAR TCPs showed comparable exhaustion profiles but enhanced cytokine production and prolonged cytotoxic function across repeated antigen challenges. These findings identify FOXP3 as a context-dependent modulator of CAR T cell function and suggest that its disruption may enhance therapeutic potency without exacerbating exhaustion. FOXP3 targeting may represent a complementary strategy to improve the functional resilience of CAR T cell therapies in cancer or autoimmune disease.

Keywords:  CAR T cell potency; CAR T cells; CRISPR-Cas9; FOXP3; T cell exhaustion; cytotoxicity; effector T cells; gene editing; immunomodulation; immunotherapy

DOI:  https://doi.org/10.1016/j.omtm.2025.101570
Front Immunol. 2025 ;16 1658970

Diagnosis of cancer, autoimmune and infectious diseases and prediction of the therapy effectiveness based on the individual's immunotype.

Dmitry V Tabakov, Anna A Maznina, Ekaterina A Astakhova, Anastasia E Egorova, Elena N Zakharova, Olga V Glushkova, Ekaterina S Petriaikina, Dmitry V Svetlichnyy, Julia A Krupinova, Viktor P Bogdanov, Vladimir S Yudin, Anton A Keskinov, Sergey M Yudin, Mary Woroncow, Veronika I Skvortsova, Pavel Yu Volchkov.

  Immune system plays a central role in the pathogenesis of cancer and autoimmune diseases. An entire field has emerged to identify separate minor cell subpopulations carrying potential molecular targets or activation markers to study their prognostic role in disease progression and severity or predictive potential to use immunotherapy. However, the biomarker potential of minor populations is limited, as it does not take into account systemic interactions between populations of the immune system. A number of studies in the COVID era have shown that the certain balance between immune cell populations in donor's blood, called 'immunotype', can predict the outcome of treatment and the onset of a cytokine storm. This observation was extended to other diseases, including cancer and autoimmunity. It was shown that the immunotype can be used to diagnose both the presence of the disease itself, as well as its form or progression, to stratify patients in the risk groups and to predict the effectiveness of therapy. The most important advantages of immunotype-based diagnostics are its low invasiveness, the possibility of multiple biomaterial sampling, and the complexity of the analysis by the simultaneous assessment of blood cell composition and their functional activity. In this review, we summarize currently available studies of immunotypes and defined key subpopulations, their possible impact in diagnostics and personalization of the therapy in clinical routine practice in various diseases.

Keywords:  autoimmune disease; cancer; immune system; immunophenotyping; immunotype

DOI:  https://doi.org/10.3389/fimmu.2025.1658970
Cancer Cell. 2025 Sep 18. pii: S1535-6108(25)00364-2. [Epub ahead of print]

Rewiring natural killer cells for next-generation cancer therapies.

Aline Pfefferle, Karl-Johan Malmberg.

Harnessing the cytotoxic potential of natural killer (NK) cells for cancer immunotherapy has proven challenging. In this issue of Cancer Cell, Biederstädt et al. and Nikolic et al. utilize genome-wide CRISPR screening to uncover novel regulators of NK cell function, paving the way for developing next-generation NK cell therapies.

DOI: https://doi.org/10.1016/j.ccell.2025.08.007
Drug Des Devel Ther. 2025 ;19 7837-7852

Rheumatoid Arthritis Therapy Based on B Cells.

Yongqi Liang, Menglei Zha, Qifeng Liu, Zhifei Lai, Lei Li, Yiming Shao, Jianbo Sun.

  Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent synovial inflammation, joint destruction, and progressive disability. While current therapeutic approaches-including corticosteroids, disease-modifying antirheumatic drugs (DMARDs), nonsteroidal anti-inflammatory drugs (NSAIDs), and biologic agents-provide symptomatic relief, their clinical utility remains constrained by substantial limitations such as systemic toxicity, drug resistance, and cumulative adverse effects. These challenges underscore the critical need for novel therapeutic strategies with improved safety and efficacy profiles. The pathogenesis of RA involves multifaceted immune dysregulation, with emerging evidence highlighting the central role of B lymphocytes in both disease initiation and progression. Although B cell-targeted therapies like rituximab demonstrate clinical efficacy, unanswered questions persist regarding the precise immune functions of B cell subpopulations in RA pathogenesis and their potential as translatable therapeutic targets. This comprehensive review examines the clinical burden of RA, limitations of conventional therapies, and the evolving understanding of B cell pathophysiology. We critically evaluate established B cell-directed interventions-including B cell depletion, B cell functional modulation, and regulatory B cell (Breg) promotion-while exploring innovative nanofabrication technologies that may overcome current therapeutic barriers. By synthesizing recent advances in immunomodulatory research, this analysis aims to inform future directions for targeted RA management.

Keywords:  B cells; RA; antigen presentation; immune regulation; targeted therapy

DOI:  https://doi.org/10.2147/DDDT.S527687
Cytotherapy. 2025 Aug 20. pii: S1465-3249(25)00809-6. [Epub ahead of print]

Development and qualification of a sensitive method for residual feeder cell detection in NK cell therapy products.

Elizabeth Castro-Rivera, Alexandra Aquino-Acevedo, Li Chen, Myraida Toledo-Rojas, Kevin Avilés-Padilla, Daphne Ayala-Torres, Eliezer Romeu-Bonilla, Lei Zhang, Tania Rodriguez, Ivone Bruno.

  Cellular therapies must meet stringent regulatory standards for safety and quality. These requirements include the thorough evaluation of all manufacturing components, particularly residual cellular materials, and the potential impact of their presence in the final product. In this study we describe the development and qualification of a safety test method that supports the release of a Natural Killer (NK) cells drug product that is expanded by activation through a combination of cytokines and interaction with feeder cells, derived from a monoclonal K-562 cell line, modified to express 4-1BBL and mbIL-21 genes. In response to the safety and regulatory requirements with the use of feeder cells in NK cell manufacturing for clinical applications, and the limitation of current methodologies, we developed a residual test method enhanced by whole-genome sequencing and copy number analysis via droplet digital PCR (ddPCR). The method guarantees accurate identification of target cells via copy number with high specificity and precision with a coefficient of variation of <10%, linearity (R2 = 0.999), and accuracy (72-115% recovery). The linear range reached a lower limit of quantification (LLOQ) of 0.1% and a lower limit of detection (LLOD) of 0.02%. These results support the applicability of this method for residual cell detection and release testing of cellular immunotherapies. Importantly, the methodological framework described here is broadly applicable and can be adapted for other cell therapy products where residual unwanted cells pose a risk of contamination in the final product, offering an adaptable, sensitive, and regulatory-compliant solution for safety testing.

Keywords:  cell therapy product; ddPCR; feeder cells; method qualification; residual detection; safety assay

DOI:  https://doi.org/10.1016/j.jcyt.2025.08.002
Immunotargets Ther. 2025 ;14 997-1014

T Cells Dysfunction in Multiple Myeloma.

Linyu Cai, Liping Zuo, Guangqi Wang, Qun Li, Chi Ma, Jianghua Wu, Chunyan Sun, Yu Hu.

  Multiple myeloma (MM) is a kind of plasma cell hematologic malignancy. Notable advancements in patient survival have been achieved due to the clinical application of anti-CD38 monoclonal antibody, chimeric antigen receptor T cells (CAR-T) and bispecific T cell engagers (TCEs). However, the immunosuppressive microenvironment of the bone marrow hinders the effectiveness of these novel immunotherapies, consequently restricting their efficacy. Hence, it is imperative to clarify the exact mechanisms to devise strategies aimed at improving the efficacy of immunotherapy. In this review, we provide a systematic overview of recent research concerning the different T cell subtypes in the immune evasion mechanisms of MM. The review emphasizes the imbalance between the immune surveillance and the immune suppression, and highlight recent studies about unconventional T cells, the metabolic control of immune reactions, and novel therapeutic strategies aimed at addressing immune evasion mechanisms that promote the progression of MM.

Keywords:  CTL; Th17; Treg; immune escape; immunosuppressive cells; multiple myeloma

DOI:  https://doi.org/10.2147/ITT.S534784
Front Immunol. 2025 ;16 1643418

Skin immune microenvironment in psoriasis: from bench to bedside.

Yi Yao, Li-Qing Chen, Yi-Bo Lv, Shun-Li Tang, Wei Shen, Hui Sun, Hua-Jie Zhong.

  Psoriasis, a chronic immune-mediated inflammatory skin disorder affecting approximately 2-3% of the global population, manifests in distinct forms including plaque, pustular, and erythrodermic types. The pathogenesis involves complex interactions between genetic susceptibility, epigenetic modifications, and environmental triggers that disrupt immune homeostasis, particularly within the skin's epithelial immune microenvironment (EIME). This review examines the fundamental mechanisms of psoriasis from a 'bench' perspective, encompassing genetic triggers, immune cell contributions, cytokine cascades, and insights derived from multi-omics studies. It also incorporates emerging areas such as gut microbiota dysbiosis and neuro-immunological influences. Translational research linking these discoveries to clinical application is discussed, covering biomarker identification, comorbidity management, and the advancement of novel therapies. At the 'bedside', we evaluate current conventional treatments, targeted biologic agents (e.g., TNF-α, IL-17, and IL-23 inhibitors), and emerging modalities including JAK inhibitors, epigenetic modulators, and stem cell therapies. Challenges pertaining to efficacy, safety, and personalized medicine are addressed, alongside future directions emphasizing multi-omics integration and holistic immune targeting. Highlighting the critical role of the immune microenvironment, this narrative review underscores the translational progress driving towards improved patient outcomes.

Keywords:  biologics; cytokines; gut microbiota; immune microenvironment; neuroimmunology; pathogenesis; psoriasis; translational research

DOI:  https://doi.org/10.3389/fimmu.2025.1643418
Int Immunopharmacol. 2025 Sep 17. pii: S1567-5769(25)01543-7. [Epub ahead of print]166 115552

Nanobody therapeutics in autoimmune and immune-mediated inflammatory diseases: experimental insights and translational strategies.

Rana Sherbaevna Salieva.

  Nanobodies, single-domain-based VHHs, are antibody fragments derived from heavy-chain-only IgG antibodies found in the Camelidae family that provide marked advantages compared to traditional monoclonal antibodies. Their small molecular size, simple structure, and high antigen-binding affinity facilitate the precise modulation of immune pathways associated with autoimmune pathophysiology. This review integrates ongoing advancements in experimental and translational research on nanobody therapeutics, encompassing multiple autoimmune conditions, including systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and type 1 diabetes. Focus is given to preclinical evaluation using disease models, highlighting critical immunological targets suitable for nanobody-based targeting and assessing data from early-phase clinical trials. An extensive literature review was performed through leading biomedical databases, including Scopus, PubMed, and ClinicalTrials.gov, centered on preclinical studies, disease models, and initial clinical studies available until 2025. Preclinical data support the compelling effectiveness of nanobodies in regulating critical immune targets, including IL-6, BAFF, TNF-α, and integrins, leading to suppression of systemic and tissue-specific inflammatory responses in experimental models. Early-phase studies highlight well-tolerated safety outcomes demonstrating beneficial therapeutic effects, validating the promise of nanobody therapeutics for clinical translation. This detailed synthesis reveals the pathway to clinical translation of nanobody therapeutics in autoimmune diseases, outlining a pathway for subsequent clinical applications and the advancement of next-generation biologic therapies.

Keywords:  Autoimmune diseases; Immunotherapy; Nanobodies; Single-domain antibodies; Translational research

DOI:  https://doi.org/10.1016/j.intimp.2025.115552
Br J Radiol. 2025 Sep 20. pii: tqaf233. [Epub ahead of print]

Disparities in Imaging and Management of Multiple Sclerosis: A Review.

Alvin Tran, George F Grant, Olutola P Akande, Gelareh Sadigh.

  Despite advancements in multiple sclerosis (MS) imaging and treatment, there are sex-specific differences and disparities across sociodemographic factors (e.g., race, ethnicity, socioeconomic status, health literacy, and geography) that can result in disparate clinical presentation, diagnosis, management, and outcomes. These social determinants of health often intersect, limiting access to MRI or disease-modifying therapies. Financial and geographic barriers can delay diagnosis and treatment, particularly in rural or underserved areas. Patients with low health literacy may have difficulty navigating care, while provider-related factors, like implicit biases and varying practices in low-resource settings, contribute to unequal imaging and treatment utilization. Radiologists are uniquely positioned to help reduce these inequities. By collaborating with clinical teams, standardizing imaging protocols, and expanding access through extended service hours and patient navigation programs, radiology practices can address many barriers. Subspecialized neuroradiology expertise, delivered through teleradiology, can help mitigate diagnostic disparities in underserved regions. Radiologists can support health equity by engaging in community outreach to improve health literacy and by working to increase workforce diversity. This review examines the intersection of clinical and radiologic disparities in MS, identifies key barriers to imaging access and utilization, and highlights how radiology can promote equitable MS care to improve outcomes across all populations.

Keywords:  Diagnostic Imaging; Health Disparities; Multiple Sclerosis; Social Determinants of Health

DOI:  https://doi.org/10.1093/bjr/tqaf233
Front Immunol. 2025 ;16 1665688

Decoding paraneoplastic neuromyelitis optica: a multi-omics investigation of tumor-driven T and B cell dynamics.

Wenjing Huang, Ruyu Lin, Xianyi Zeng, Hai Wang, Jichun Yan.

  A significant subset of Neuromyelitis Optica Spectrum Disorder (NMOSD) cases occurs as a paraneoplastic syndrome, where an underlying tumor triggers a devastating autoimmune attack against the central nervous system. This autoimmune response is driven by pathogenic aquaporin-4 autoantibodies (AQP4-IgG), likely initiated by the tumor's expression of AQP4 in a phenomenon of molecular mimicry. Understanding the precise immune mechanisms that link a patient's cancer to their neurological disease is critical for early diagnosis of the occult malignancy and for improved patient outcomes. This review explores how multi-omics technologies are revolutionizing the investigation of T and B cell functional dynamics in this specific context, offering unprecedented resolution into the pathogenesis of paraneoplastic NMOSD. The application of integrated multi-omics-including genomics, epigenomics, transcriptomics (particularly single-cell RNA-seq), proteomics, and metabolomics-provides a holistic framework to dissect the specific immune response directed against both the tumor and the CNS. Transcriptomics, notably scRNA-seq, can deconstruct the heterogeneity of tumor-infiltrating and circulating T and B cells to identify the pathogenic subsets responsible for the autoimmune pathology. Proteomics can aid in identifying tumor-specific biomarkers, while metabolomics offers insights into the metabolic vulnerabilities of the autoreactive immune cells. Multi-omics analyses reveal the cellular and molecular cascade of the paraneoplastic response. High-throughput T-cell receptor (TCR) and B-cell receptor (BCR) sequencing provides direct evidence of oligoclonal expansions, identifying the specific T and B cell clones that likely recognize shared AQP4 epitopes on both the cancer cells and CNS astrocytes. These expanded B cells show hallmarks of a mature, antigen-driven response, including class-switching and affinity maturation of the pathogenic AQP4-IgG. Furthermore, analyses of T cell dynamics reveal a pro-inflammatory environment, with functional impairment of regulatory T cells (Tregs) and a skewed balance towards Th17 and Th1 cells, which is likely initiated by the tumor and perpetuated in the CNS via critical T-B cell interactions, such as the IFN-I → B-cell → IL-6 → pathogenic Th17 axis. Despite these insights, substantial challenges remain in translating these findings into clinical practice. A key hurdle is using multi-omics to develop a reliable molecular signature that can distinguish paraneoplastic from idiopathic NMOSD at diagnosis, thereby streamlining cancer screening for high-risk patients. Advanced computational tools, including AI and machine learning, are needed to integrate the immense volume of data and identify the subtle differences. Future research must prioritize the analysis of longitudinal samples (before and after tumor treatment) and the functional validation of the identified pathogenic pathways. In conclusion, multi-omics is profoundly enhancing our understanding of how tumors can initiate and sustain a specific, targeted autoimmune response in paraneoplastic NMOSD. This deep mechanistic investigation not only promises to improve diagnostics and personalized therapies for these complex patients but also serves as a powerful model for understanding other paraneoplastic syndromes, ultimately bridging the fields of oncology and neuroimmunology.

Keywords:  Neuromyelitis optica spectrum disorder (NMO-SD); aquaporin-4 autoantibodies; multi-omics technologies; paraneoplastic syndrome; pathogenesis

DOI:  https://doi.org/10.3389/fimmu.2025.1665688
Front Immunol. 2025 ;16 1637539

Revolutionizing tumor diagnosis and treatment: the promise of DNA nanotechnology.

Yi Zhou, Ning Wang.

  Tumors represent a significant challenge to human health, with ongoing difficulties in their diagnosis and treatment. Over recent decades, DNA nanotechnology has emerged as a promising field, demonstrating substantial advancements in drug delivery and disease diagnosis. The inherent biocompatibility and programmability of DNA nanostructures allow for their tailored design and assembly, facilitating the delivery of various therapeutic agents. Due to their ease of modification, these nanostructures can be functionalized to recognize specific targets, enabling the targeted drug delivery and minimizing the adverse effects. Furthermore, DNA nanotechnology contributes to the rapid and sensitive detection of tumor biomarkers, enhancing the early-stage diagnosis of malignant tumors. This article comprehensively reviews advancements in DNA nanomaterial applications for tumor diagnosis and treatment. First of all, in the aspect of tumor diagnosis, this review focuses on the research of DNA nanostructures in the detection of tumor biomarkers, and then introduces the application of DNA nanostructures in tumor therapy, including chemotherapy, gene therapy and immunotherapy. Finally, we summarized the challenges and opportunities of DNA nanomaterials in biomedical research and clinical applications. This review systematically organizes key innovations: (1) first comprehensive analysis of DNA nanostructures design principles for the applications in tumor diagnosis and therapy, and (2) original proposal for overcoming clinical translation barriers through precise design and assembly of DNA nanostructures.

Keywords:  DNA nanostructures; aptamer; nanomedicine; tumor diagnosis; tumor therapy

DOI:  https://doi.org/10.3389/fimmu.2025.1637539