bims-carter Biomed News
on CAR-T Therapies
Issue of 2025–05–04
twenty-two papers selected by
Luca Bolliger, lxBio
  1. Strategies to overcome tumour relapse caused by antigen escape after CAR T therapy.
  2. CAR-T Therapy for the Treatment of Colorectal Cancer.
  3. The Improving Outcomes in Relapsed-Refractory Diffuse Large B Cell Lymphoma: The Role of CAR T-Cell Therapy.
  4. Tailoring CAR surface density and dynamics to improve CAR-T cell therapy.
  5. From molecular design to clinical translation: dual-targeted CAR-T strategies in cancer immunotherapy.
  6. Improvement in the function of self-activating chimeric antigen receptor by replacing the linker sequence.
  7. Enhancing the physiological characteristics of chimeric antigen receptor natural killer cells by synthetic biology.
  8. Easy as ABC: Managing Toxicities of Antibody-Drug Conjugates, Bispecific Antibodies, and CAR T-Cell Therapies.
  9. Revolutionizing Immunotherapy: The Next Frontier in CAR T-Cell Engineering.
  10. Frequently Asked Questions on Imaging in Chimeric Antigen Receptor T-Cell Therapy Clinical Trials.
  11. Cost-effective strategies for CAR-T cell therapy manufacturing.
  12. Identification of Adjustment Variables in Indirect Comparisons: A Rapid Review of CAR-T Therapies for Diffuse Large B-Cell Lymphoma.
  13. CAR-T cell therapy in rheumatic diseases: a review article.
  14. Targeting Intracellular Innate RNA-Sensing Systems Overcomes Resistance to CAR T Cell Therapy in Solid Tumors.
  15. Age reprogramming: Innovations and ethical considerations for prolonged longevity (Review).
  16. Targeting DLL3: Innovative Strategies for Tumor Treatment.
  17. Chimeric antigen receptor NK cells for breast cancer immunotherapy.
  18. The Role of NK Cells in Cancer Immunotherapy: Mechanisms, Evasion Strategies, and Therapeutic Advances.
  19. Gut reactions: harnessing microbial metabolism to fuel next-generation cancer immunotherapy.
  20. Single-cell sequencing combined with bulk RNA seq reveals the roles of natural killer cell in prognosis and immunotherapy of hepatocellular carcinoma.
  21. Go to the scene: TH9 cells superior migration ability to the lungs explains their exceptional anticancer efficacy.
  22. Tissue Engineering and Regenerative Medicine: Perspectives and Challenges.
  1. Mol Cancer. 2025 Apr 28. 24(1): 126
    Strategies to overcome tumour relapse caused by antigen escape after CAR T therapy.
    Yufei Lu, Fu Zhao.
      Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of B cell and plasma cell malignancies, and numerous promising targets against solid tumours are being explored. Despite their initial therapeutic success in hematological cancers, relapse occurs in a significant fraction of patients, highlighting the need for further innovations in advancing CAR T cell therapy. Tumour antigen heterogeneity and acquired tumour resistance leading to antigen escape (antigen loss/downregulation) have emerged as a crucial factor contributing to immune escape and CAR T cell resistance, particularly in the case of solid tumours with only limited success achieved to date. In this review, we discuss mechanisms of tumour relapse in CAR T cell therapy and the promising strategies that are under development to overcome multiple resistance mechanisms, thereby reducing outgrowth of antigen escape variants. Specifically, we emphasize the importance of designing clinical translational strategies to enhance CAR T cell crosstalk with host immune cells, eliciting endogenous antitumour immune responses through antigen/epitope spreading, which offers a genuine solution to the limitations of targeting tumour antigen heterogeneity in solid tumours with monospecific T cell therapies.
    Keywords:  Antigen loss/downregulation; Antigen/epitope spreading; Chimeric antigen receptor; Tumour heterogeneity
    DOI:  https://doi.org/10.1186/s12943-025-02334-6
  2. Discov Med. 2025 Apr;37(195): 618-630
    CAR-T Therapy for the Treatment of Colorectal Cancer.
    Arturo Lecumberri, Hugo Arasanz, Irene Caseda, Ana Elsa Huerta, Natalia Castro, Ibone Labiano, Maria Alsina, Natalia Ramirez, Ruth Vera.
      Colorectal cancer (CRC) is one of the most common malignancies worldwide. Advanced CRC has a poor prognosis, with treatment primarily relying on chemotherapy combined with targeted therapies. Currently, immunotherapy based on immune checkpoint inhibitors is reserved exclusively for mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumors, which represent less than 10% of advanced CRC cases. Chimeric antigen receptor (CAR)-T cell therapy is a type of adoptive cell therapy involving modified T-lymphocytes engineered to express chimeric antigen receptors, enabling them to recognize surface antigens expressed by tumor cells. CAR-T cell therapy has demonstrated efficacy in treating hematological malignancies such as lymphoma, myeloma, and leukemia. However, its efficacy in solid tumors remains limited due to several limitations such as antigen heterogeneity, restricted CAR-T cell trafficking into the tumor area, and the presence of an immunosuppressive tumor microenvironment. Developing novel CAR-T cell therapies for solid tumors represents an unmet need, particularly for cases where immune checkpoint blockade is ineffective, such as CRC. Preclinical studies have shown the efficacy of various CAR-T cell models targeting a wide range of tumor-associated antigens in CRC, both in vitro and in vivo. Despite these promising results, the clinical efficacy of CAR-T cell therapy for CRC has been limited in early-phase clinical trials. Factors such as trial design or tumor characteristics, including antigen heterogeneity and the immunosuppressive microenvironment, should be considered. The development of innovative CAR-T cell models and the identification of novel antigens may improve the effectiveness of CAR-T cell therapy for CRC patients.
    Keywords:  CAR-T cell therapy; chimeric antigen receptor; colorectal cancer; immunotherapy; tumor-associated antigen
    DOI:  https://doi.org/10.24976/Discov.Med.202537195.54
  3. Curr Treat Options Oncol. 2025 Apr 28.
    The Improving Outcomes in Relapsed-Refractory Diffuse Large B Cell Lymphoma: The Role of CAR T-Cell Therapy.
    Vibor Milunović, Dora Dragčević, Martina Bogeljić Patekar, Inga Mandac Smoljanović, Slavko Gašparov.
       OPINION STATEMENT: Diffuse large B cell lymphoma, not otherwise specified (DLBCL-NOS) is the most common aggressive lymphoma and can be cured with CHOP-R immunochemotherapy in 60% of cases. The second-line therapy includes salvage regimens followed by autologous stem cell transplantation (ASCT), which offers a cure to a minority of patients due to limitations in efficacy and eligibility. These data present the unmet need in the field, and this review article focuses on how second-generation chimeric antigen receptor T (CAR T) cell therapy targeting CD19 antigen may improve the outcomes with relapsed/refractory DLBCL. In heavily pretreated patients, who have dismal outcomes with conventional therapy, all three approved products-tisangenlecleucel (tisa-cel), axicabtagene ciloleucel (axi-cel), and lisocabtagene maraleucel (liso-cel) have shown durable, unprecedented complete responses with the potential for cure. When compared to salvage regimens and ASCT as the standard of care, axi-cel and liso-cel, unlike tisa-cel, have demonstrated superiority in long-term control. In ASCT-ineligible r/r DLBCL, liso-cel has shown a favourable benefit-risk ratio. Regarding safety, two adverse events of interest have emerged: cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, both of which are manageable. Real-world evidence reflects the results of pivotal trials while favouring axi-cel in heavily pretreated patients, albeit with higher toxicity. The main barrier to the implementation of this treatment modality is the cost associated with the process of CAR T therapy, along with complications and reimbursement issues. However, the barriers can be overcome, and CAR T therapy has the potential to become the standard of care in relapsed/refractory DLBCL. Furthermore, with advances in the scientific engineering of CAR products and the understanding of novel treatment modalities currently being tested in clinical trials, we believe that targeted cellular therapy will become the future of relapsed/refractory DLBCL treatment.
    Keywords:  Autologous transplantation; CAR T-cell therapies; Clinical trials; Diffuse large B-cell lymphoma; Not otherwise specified; Safety
    DOI:  https://doi.org/10.1007/s11864-025-01305-9
  4. J Immunother Cancer. 2025 Apr 29. pii: e010702. [Epub ahead of print]13(4):
    Tailoring CAR surface density and dynamics to improve CAR-T cell therapy.
    Ana Hinckley-Boned, Carmen Barbero-Jiménez, Maria Tristán-Manzano, Noelia Maldonado-Perez, Michael Hudecek, Pedro Justicia-Lirio, Francisco Martin.
      Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment landscape for relapsed and/or refractory B-cell neoplasms, garnering Food and Drug Administration/European Medicines Agency approval for six commercial products. Despite this success, challenges persist, including a relapse rate of 30-50% in hematologic tumors, limited clinical efficacy in solid tumors, and severe side effects. This review addresses the critical need for therapeutic enhancement by focusing on the often-overlooked strategy of modulating CAR protein density on the cell membrane. We delve into the key factors influencing CAR surface expression, such as CAR downmodulation following antigen encounter and antigen-related factors. The dynamics of CAR downmodulation remain underexplored; however, recent data point to its modification as a useful tool for improving functionality. Notably, transcriptional control of CAR expression and the incorporation of specific elements into the CAR design have emerged as interesting strategies to tailor CAR expression profiles. Therefore, controlling CAR dynamic density may represent an attractive strategy for achieving optimal therapeutic outcomes.
    Keywords:  Antigen receptor design; Chimeric antigen receptor - CAR; Immunotherapy; Solid tumor; T cell Receptor - TCR
    DOI:  https://doi.org/10.1136/jitc-2024-010702
  5. Int J Biol Sci. 2025 ;21(6): 2676-2691
    From molecular design to clinical translation: dual-targeted CAR-T strategies in cancer immunotherapy.
    Zhenrong Wang, Mengyi Wang, Mengting Wang, Ruijie Zhou, Xiaotong Deng, Xin Ouyang, Minghui Chu, Xinyu Wei, Lei Yang, Jinbiao Liu, Yao Xu.
      The pathogenesis of tumors involves various abnormalities at both the cellular and genetic levels. Chimeric antigen receptor (CAR)-T cell immunotherapy has emerged as a transformative treatment strategy that effectively addresses these challenges. While CAR-T therapy has shown remarkable success in treating hematological malignancies, limitations have been identified, particularly in single antigen-targeting CAR-T therapies. These limitations include antigenic mutation or loss, reduced efficacy against leukemia, and poor results in solid tumors due to factors like low CAR-T cell persistence, limited tumor infiltration, rapid cell exhaustion, the suppressive tumor microenvironment, and heterogeneous tumor antigen expression. In recent years, multi-antigen targeted CAR-T therapies have garnered significant attention for their potential to prevent tumor relapse and progression. This review outlines the fundamental design of dual CAR structures and summarizes the major advancements in both preclinical studies and clinical trials of dual-targeted CAR-T cell therapy, categorized by cancer type. Additionally, it discusses the challenges associated with dual-targeted CAR-T therapy and the strategies to enhance its efficacy and applicability in treating both hematologic and solid tumors. In conclusion, the progress in dual-targeted CAR-T cell therapy presents a promising therapeutic avenue for multiple malignancies, offering insights into future modifications of immunotherapy to advance the field.
    Keywords:  CAR-T cell therapy; dual target; immunotherapy; leukemia; solid tumor
    DOI:  https://doi.org/10.7150/ijbs.108036
  6. Front Immunol. 2025 ;16 1502607
    Improvement in the function of self-activating chimeric antigen receptor by replacing the linker sequence.
    Taku Kouro, Daisuke Hoshino, Yasunobu Mano, Shoutaro Tsuji, Hidetomo Himuro, Kohzoh Imai, Tetsuro Sasada.
      Chimeric antigen receptor (CAR)-T cell therapy is an effective treatment for hematological cancers; however, challenges remain in its application to solid tumors. Among these, the control of CAR-T cell exhaustion is important. The relationship between tonic signals generated by the CAR self-activation and CAR-T cell exhaustion has attracted considerable attention. The magnitude of the tonic signal is known to depend on the structure of the extracellular portion of CAR, but the role of the linker sequence of the single-chain variable region (scFv) in the tonic signal and function in CAR-T cells has not been clarified. In this study, we compared two scFv linkers, G4S and Whitlow/218, in self-activating SKM-CAR, which recognized a malignant mesothelioma-specific modified HEG1 molecule. We observed no differences in cell surface phenotypes, NFAT and NFκB signaling intensities, and gene expression profiles between SKM-CAR T cells with these different linkers. However, switching from the G4S to the Whitlow/218 linker in SKM-CAR-T cells with the CD28 co-stimulatory domain significantly altered cytokine expression after antigen stimulation and improved the in vitro tumor cell killing activity, but not the in vivo tumor control. This is the first study describing the advantages of the Whitlow/218 linker over the G4S linker for some aspects of CAR-T cell function.
    Keywords:  CAR-T; T cell exhaustion; cancer immunotherapy; scFv; tonic signaling
    DOI:  https://doi.org/10.3389/fimmu.2025.1502607
  7. Front Immunol. 2025 ;16 1592121
    Enhancing the physiological characteristics of chimeric antigen receptor natural killer cells by synthetic biology.
    Shuochao Ji, Cheng Jin, Xinjiang Cui.
      Chimeric antigen receptor natural Killer (CAR-NK) cells therapy represents a next-generation immunotherapeutic approach following CAR-T cells therapy, offering inherent "off-the-shelf" compatibility and mitigated off-tumor toxicity. Despite these advantages, clinical translation remains constrained by poor in vivo persistence and functional exhaustion in immunosuppressive tumor microenvironments (TME). This review examines recent advancements in synthetic biology aimed at enhancing the physiological characteristics of CAR-NK cells. By delineating the synergy between NK cells and synthetic biology toolkits, this work provides a roadmap for developing next-generation CAR-NK therapies capable of addressing solid tumor challenges while maintaining favorable safety profiles.
    Keywords:  NK cells; TME; chimeric antigen receptor; immunotherapy; synthetic biology
    DOI:  https://doi.org/10.3389/fimmu.2025.1592121
  8. Am Soc Clin Oncol Educ Book. 2025 Jun;45(3): e473916
    Easy as ABC: Managing Toxicities of Antibody-Drug Conjugates, Bispecific Antibodies, and CAR T-Cell Therapies.
    Michael D Jain, Jeremy S Abramson, Stephen M Ansell.
      Antibody-drug conjugates (ADCs), bispecific antibodies that engage T cells (BsAbs), and chimeric antigen receptor (CAR) T cells are widely used standard-of-care therapies that have revolutionized the treatment of lymphoid and plasma cell malignancies. With recent regulatory approvals, these therapies are poised to also revolutionize the treatment of common solid tumors and become a part of the everyday lexicon, the ABCs, of the practicing oncologist. Drawing from experience in hematology, we review the early, late, and rare toxicities of ADCs, BsAbs, and CAR T cells and provide general principles for their management.
    DOI:  https://doi.org/10.1200/EDBK-25-473916
  9. Crit Rev Oncol Hematol. 2025 Apr 28. pii: S1040-8428(25)00139-8. [Epub ahead of print] 104751
    Revolutionizing Immunotherapy: The Next Frontier in CAR T-Cell Engineering.
    Anuupama Suchiit, Subash Sonkar.
      Chimeric Antigen Receptor (CAR) T-cell therapy has emerged as a groundbreaking immunotherapy, offering new hope for cancer treatment, particularly in hematologic malignancies. This review explores the development of CAR T-cell therapy from its first-generation design, which laid the foundational structure, to advanced fifth-generation CARs that integrate sophisticated synthetic biology. Each generation of CARs has introduced critical improvements, such as the incorporation of costimulatory domains, dual signaling pathways, and cytokine release mechanisms to enhance T-cell activation, persistence, and efficacy. Current applications of CAR T-cell therapy have seen significant success in treating cancers like acute lymphoblastic leukemia and diffuse large B-cell lymphoma, with several therapies gaining regulatory approval. However, challenges persist in targeting solid tumors due to the immunosuppressive tumor microenvironment and antigen heterogeneity. Ongoing clinical trials and research are focused on overcoming these barriers through next-generation CAR designs, novel antigen targets, and combination therapies. The review highlights recent advancements, emerging targets, and the potential of CAR T-cell therapy to revolutionize cancer treatment, paving the way for more effective and personalized approaches.
    Keywords:  CAR T-cell therapy; T-cell engineering; antigen escape; clinical trials; cytokine release syndrome; gene editing; hematologic malignancies; immunotherapy; solid tumors; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.104751
  10. Korean J Radiol. 2025 May;26(5): 471-484
    Frequently Asked Questions on Imaging in Chimeric Antigen Receptor T-Cell Therapy Clinical Trials.
    Sang Eun Won, Eun Sung Lee, Chong Hyun Suh, Sinae Kim, Hyo Jung Park, Kyung Won Kim, Jeffrey P Guenette.
      Clinical trials for chimeric antigen receptor (CAR) T-cell therapy are in the early stages but are expected to progress alongside new treatment approaches. This suggests that imaging will play an important role in monitoring disease progression, treatment response, and treatment-related side effects. There are, however, challenges that remain unresolved, regarding imaging in CAR T-cell therapy. We herein discuss the role of imaging, focusing on how tumor response evaluation varies according to cancer type and target antigens in CAR T-cell therapy. CAR T-cell therapy often produces rapid and significant responses, and imaging is vital for identifying side effects such as cytokine release syndrome and neurotoxicity. Radiologists should be aware of drug mechanisms, response assessments, and associated toxicities to effectively support these therapies. Additionally, this article highlights the importance of the Lugano criteria, which is essential for standardized assessment of treatment response, particularly in lymphoma therapies, and also explores other factors influencing imaging-based evaluation, including emerging methodologies and their potential to improve the accuracy and consistency of response assessments.
    Keywords:  Chimeric antigen receptor T-cell (CAR T-cell) therapy; Complications; Imaging; Lugano criteria; Tumor response assessment
    DOI:  https://doi.org/10.3348/kjr.2024.1126
  11. Mol Ther Oncol. 2025 Jun 18. 33(2): 200980
    Cost-effective strategies for CAR-T cell therapy manufacturing.
    Luiza Abdo, Leonardo Ribeiro Batista-Silva, Martín Hernán Bonamino.
      CAR-T cell therapy has revolutionized cancer treatment, with approvals for conditions like acute B-leukemia, large B cell lymphoma (LBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and multiple myeloma. However, its high costs limit accessibility. Key factors driving these costs include the need for personalized, autologous treatments, transportation to specialized facilities, reliance on viral vectors requiring advanced laboratories, and lengthy cell expansion processes. To address these challenges, alternative strategies aim to simplify and reduce production complexity. Non-viral vectors, such as Sleeping Beauty, piggyBac, and CRISPR, delivered via nanoparticles or electroporation, present promising solutions. These methods could streamline manufacturing, eliminate the need for viral vectors, and reduce associated costs. Furthermore, shortening cell expansion periods and optimizing protocols could significantly accelerate production. An emerging approach involves using genetically edited T cells from healthy donors to create universal CAR-T products capable of treating multiple patients. Finally, decentralized point-of-care (POC) manufacturing of CAR-T cells minimize logistical expenses, eliminating the need for complex infrastructure, and enabling localized production closer to patients. This innovative strategy holds potential for broadening access and reducing costs, representing a step toward democratizing CAR-T therapy. Combined, these advances could make this groundbreaking treatment more feasible for healthcare systems worldwide.
    Keywords:  B cell tumor; CAR-T cell; MT: Regular Issue; cost-effective; immunotherapy; manufacturing
    DOI:  https://doi.org/10.1016/j.omton.2025.200980
  12. Cancers (Basel). 2025 Apr 15. pii: 1335. [Epub ahead of print]17(8):
    Identification of Adjustment Variables in Indirect Comparisons: A Rapid Review of CAR-T Therapies for Diffuse Large B-Cell Lymphoma.
    Sybille Riou, Stefanie Rungaldier, Jörg Mahlich.
      Background: Chimeric antigen receptor T-cell (CAR-T) therapies have been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of diffuse large B-cell lymphoma (DLBCL), primarily based on single-arm trials or indirect comparisons with stem cell transplantation. However, no direct head-to-head comparisons of CAR-T therapies have been conducted, largely due to their high cost. To assess their true value, indirect treatment comparisons (ITCs) are essential. These comparisons, however, are prone to confounding biases, which necessitate careful adjustments through the identification and measurement of relevant variables. Materials and Methods: This study aims to identify the variables used for adjustment in ITCs of CAR-T therapies for DLBCL and examine the methodologies employed to select them. A rapid literature review was conducted in PubMed in September 2023, focusing on ITCs involving CAR-T therapies for DLBCL. The search was based on keywords categorized into three groups: techniques (ITCs and related terms), drugs (CAR-T therapies), and indication (DLBCL). Results: The rapid literature review identified 21 articles, of which 11 were selected for analysis. Exclusions were made for articles that did not identify confounders, were letters to editors, or addressed conditions other than DLBCL. Among the 11 selected publications, 10 did not clearly specify the methodology used to identify adjustment variables. A total of 25 potential confounders were identified across the studies, with substantial variability in the set of variables used, reflecting a lack of standardization in confounder selection. Commonly identified confounders included the number of prior treatment lines and Eastern Cooperative Oncology Group Performance Status (ECOG PS), although their inclusion as adjustment variables in ITCs was inconsistent, often due to missing data. Conclusions: While the identified confounders are clinically relevant, the methodologies for selecting them remain unclear, resulting in significant variability across studies. Additionally, key variables commonly considered in health technology assessments (HTAs), such as age, sex, and disease severity, were inconsistently incorporated into ITCs. To improve the reliability and consistency of ITC outcomes, there is a pressing need for standardized methodologies for identifying and adjusting for confounders.
    Keywords:  CAR-T therapies; confounder analysis; diffuse large B-cell lymphoma; indirect comparison; methodology; rapid literature review; real world evidence
    DOI:  https://doi.org/10.3390/cancers17081335
  13. Clin Rheumatol. 2025 Apr 26.
    CAR-T cell therapy in rheumatic diseases: a review article.
    Harshwardhan Patil, Rajath K Bharadwaj, Nilanjana Dutta, Ramaswamy Subramanian, Shiva Prasad, Mahabaleshwar Mamadapur.
      CAR-T cell therapy, a pioneering immune-modulating treatment that was initially designed for hematologic malignancies, is now being considered a potential treatment for autoimmune and rheumatic diseases. This method involves genetically engineering T cells to express chimeric antigen receptors (CARs), allowing them to target specific antigens associated with pathogenic immune cells. The review covers the possibility of CAR-T therapy in the treatment of autoimmune diseases like systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc). The therapy's ability to maintain remission by targeting autoreactive B cells in the course of disease has been an important aspect of studies involving SLE. In refractory RA, CAR-T cells also demonstrate a potential therapeutic modality in selectively killing immune cells driving the disease process. For SSc, CAR-T therapy may represent a novel therapeutic approach because it targets the dysregulated activity of B cells as well as the fibrotic processes that drive the disease pathology. Emerging evidence suggests potential applications in conditions such as Sjögren's syndrome and dermatomyositis. While CAR-T therapy promises accuracy, persistence, and the potential for long-term remission, many problems remain, including the risk of cytokine release syndrome, immune toxicity, and treatment affordability. The development of CAR-Tregs and advanced gene-editing techniques may increase the specificity and safety of therapy. In addition, clinical trials and long-term studies should be conducted to establish the efficacy, safety, and economic feasibility of this innovative approach. This review underscores the transformative potential of CAR-T therapy in the management of rheumatic diseases, particularly in refractory cases. Offering targeted immunomodulation with a minimum of systemic immune suppression, CAR-T therapy could redefine therapeutic paradigms and offer hope for improved outcomes in autoimmune diseases.
    Keywords:  Autoimmune diseases; Cell- and tissue-based therapy; Cytokine release syndrome; Dermatomyositis; Scleroderma; T-lymphocytes
    DOI:  https://doi.org/10.1007/s10067-025-07451-7
  14. Cancer Res. 2025 Apr 30.
    Targeting Intracellular Innate RNA-Sensing Systems Overcomes Resistance to CAR T Cell Therapy in Solid Tumors.
    Nardine Soliman, Tatiana Nedelko, Giada Mandracci, Stefan Enssle, Vincent Grass, Julius C Fischer, Florian Bassermann, Hendrik Poeck, Sebastian Kobold, Nadia El Khawanky, Simon Heidegger.
      Despite the remarkable success of CAR T cells in certain hematological malignancies, only modest responses have been achieved in solid tumors. Defective cell death pathways have recently been suggested as a tumor-intrinsic form of resistance to CAR T cell treatment. Here, we showed that insufficient activity of the innate RNA-sensing receptor system, RIG I/MAVS, leads to tumor cell-inherent resistance to CAR T cell attack. Active RIG-I/MAVS signaling in tumor cells primed intrinsic mitochondrial apoptosis pathways and expression of cell death receptors, which funneled into CAR T cell-triggered cell death. CAR T cell reliance on tumor-intrinsic RIG-I signaling was observed in various murine and human cancer types, independent of the CAR construct used, and the dependence was most pronounced under conditions with low target antigen expression or low effector/target ratios. RIG-I-induced pro-apoptotic priming of CAR T cell susceptibility involved auto-/paracrine type I IFN signaling loops and could spread to bystander tumor cells. Strong tumor-intrinsic RIG I/MAVS signaling imprinted an activated cytolytic phenotype on tumor-interacting CAR T cells. Agonist-mediated targeting of the RIG-I pathway in the tumor microenvironment rendered murine melanoma susceptible to CAR T cell therapy in vivo with enhanced infiltration of active CAR T cells. Together, this data identifies insufficient RIG-I/MAVS activity and associated impaired cell death signaling in malignant cells as a resistance mechanism to CAR T cells. Targeting tumor-intrinsic RIG-I is a potential strategy to sensitize solid tumors to CAR T cell treatment.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-3425
  15. Biomed Rep. 2025 Jun;22(6): 96
    Age reprogramming: Innovations and ethical considerations for prolonged longevity (Review).
    Timur Saliev, Prim B Singh.
      Age reprogramming and cellular rejuvenation therapies are revolutionizing the approach to aging and age-related diseases. These ground-breaking interventions target fundamental biological processes, including genomic instability, telomere attrition, and mitochondrial dysfunction, to restore cellular function and delay the onset of degenerative conditions. Emerging strategies such as epigenetic reprogramming, gene editing, stem cell therapy, and senolytic drugs show immense promise in extending health spans and potentially reversing aspects of aging. Despite marked progress in preclinical studies and early-stage clinical trials, translating these therapies into practical healthcare solutions presents significant challenges. Key issues include ensuring safety, optimizing delivery mechanisms, overcoming regulatory barriers, and addressing high costs. Moreover, ethical and economic considerations, such as equitable access and societal impacts, must be carefully addressed to prevent widening health disparities. The present review examines the current state of cellular rejuvenation research, highlighting both scientific advancements and the complex challenges associated with these therapies. With interdisciplinary collaboration, robust ethical frameworks, and scalable technological innovations, these therapies have the potential to transform healthcare. By shifting the focus from disease management to proactive health preservation, they offer a future where aging becomes a manageable and equitable process.
    Keywords:  CRISPR; age reprogramming; epigenetic; ethics; gene editing; rejuvenation; senolytics; stem cell therapy
    DOI:  https://doi.org/10.3892/br.2025.1974
  16. Pharmaceutics. 2025 Apr 16. pii: 520. [Epub ahead of print]17(4):
    Targeting DLL3: Innovative Strategies for Tumor Treatment.
    Hui Wang, Tong Zheng, Dan Xu, Chao Sun, Daqing Huang, Xiongxiong Liu.
      Delta-like 3 (DLL3) is an oncogenic protein aberrantly expressed in several tumors, particularly in small-cell lung cancer. DLL3-targeted therapies have recently made significant progress, demonstrating promising preclinical and clinical efficacy. This review aims to explore the mechanisms, challenges, and future opportunities associated with therapies targeting DLL3 for cancer treatment. The biological characteristics of DLL3 and its role in the Notch signaling pathway are introduced first, delving into the role of DLL3 in tumorigenesis and cancer progression. Next, current therapeutic approaches targeting DLL3 are described, including antibody-drug conjugates, T cell engagers, chimeric antigen receptor T cells, and radiopharmaceutical therapy, highlighting their effectiveness and safety in clinical trials. Despite the promising prospects, difficulties remain in the use of DLL3 as a therapeutic target due to tumor heterogeneity, the development of resistance, potential adverse effects, and barriers to patient stratification. Therefore, the potential of combination therapies, the use of innovative drug delivery systems, and ongoing clinical trial advancements are also discussed. Finally, the potential of DLL3-targeted therapies is summarized, highlighting the importance of multidisciplinary research to guide the clinical application and optimization of this emerging treatment strategy. These approaches might provide new therapeutic options, potentially starting a new era in cancer treatment.
    Keywords:  DLL3; clinical trials; solid tumor; targeted therapy
    DOI:  https://doi.org/10.3390/pharmaceutics17040520
  17. Cancer Treat Rev. 2025 Apr 23. pii: S0305-7372(25)00065-9. [Epub ahead of print]137 102943
    Chimeric antigen receptor NK cells for breast cancer immunotherapy.
    Nisha Wu, Ning Yang, Shiqi Zhang, Haoran Wu, Xuechun Fang, Wanying Lin, Yi Zhang, Xiaowei Qi, Ying Gong.
      Breast cancer, a predominant malignancy afflicting women globally, demands innovative therapeutic strategies beyond traditional treatments such as surgery, chemotherapy, radiotherapy, and endocrine therapy. Among the emerging therapies, immunotherapy has demonstrated substantial promise, particularly employing chimeric antigen receptor (CAR) technology. This review elucidates the prospect of CAR-modified natural killer (NK) cells in treating breast cancer. NK cells, vital components of the immune system, possess the capability to non-specifically target and extinguish neoplastic cells. Through genetic engineering, CAR constructs targeting specific breast cancer antigens, including HER2, EGFR, PD-L1, MSLN, and Trop2, are integrated into NK cells, thereby enhancing their tumor recognition and cytotoxicity. The review delves into the structural optimization of CAR-NK cells, discussing design elements such as scFv, hinge regions, and activation signals, and emphasizes strategies to augment CAR-NK cell functionality and persistence within the tumor microenvironment. Combining CAR-NK cells with other therapeutic modalities (such as chemotherapy and checkpoint inhibitors) is explored to enhance therapeutic efficacy. Preclinical researches emphasized the efficacy of CAR-NK cells in targeting breast cancer cells, paving the way for future clinical applications and offering hope for improved outcomes in breast cancer patients.
    Keywords:  Breast cancer; Chimeric antigen receptor; Clinical trials; Immunotherapy; Natural killer cells; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ctrv.2025.102943
  18. Biomedicines. 2025 Apr 02. pii: 857. [Epub ahead of print]13(4):
    The Role of NK Cells in Cancer Immunotherapy: Mechanisms, Evasion Strategies, and Therapeutic Advances.
    Paula Morcillo-Martín-Romo, Javier Valverde-Pozo, María Ortiz-Bueno, Maurizio Arnone, Laura Espinar-Barranco, Celia Espinar-Barranco, María Eugenia García-Rubiño.
      Background/Objectives: Natural killer (NK) cells play a crucial role in tumor surveillance by exerting cytotoxic activity and modulating immune responses. However, tumors employ diverse evasion strategies that limit NK cell effectiveness. This review aims to explore the molecular mechanisms of NK cell activation and inhibition in cancer, the influence of the tumor microenvironment, and the latest advancements in NK cell-based immunotherapies, including adoptive NK cell transfer and Chimeric Antigen Receptor-Natural Killer (CAR-NK) cell therapies. Methods: A comprehensive literature review was conducted, prioritizing peer-reviewed studies from the last decade on NK cell biology, tumor immune evasion, and immunotherapeutic applications. The analysis includes data from preclinical models and clinical trials evaluating NK cell expansion strategies, cytokine-based stimulation, and CAR-NK cell therapy developments. Results: NK cells eliminate tumors through cytotoxic granule release, death receptor pathways, and cytokine secretion. However, tumor cells evade NK-mediated immunity by downregulating activating ligands, secreting immunosuppressive molecules, and altering the tumor microenvironment. Novel NK cell-based therapies, such as CAR-NK cells and combination approaches with immune checkpoint inhibitors, enhance NK cell persistence and therapeutic efficacy against both hematologic and solid malignancies. Clinical trials suggest improved safety profiles compared to CAR-T therapies, with reduced cytokine release syndrome and graft-versus-host disease. Conclusions: While NK cell-based immunotherapies hold great promise, challenges remain, including limited persistence and tumor-induced immunosuppression. Addressing these hurdles will be critical for optimizing NK cell therapies and advancing next-generation, off-the-shelf immunotherapeutics for broader clinical applications.
    Keywords:  CAR-NK cells; adoptive cell therapy; cancer immunotherapy; cytokine-based NK cell therapy; cytotoxicity; immune checkpoint inhibitors; innate immunity; natural killer cells; tumor evasion; tumor microenvironment
    DOI:  https://doi.org/10.3390/biomedicines13040857
  19. J Immunother Cancer. 2025 Apr 29. pii: e011540. [Epub ahead of print]13(4):
    Gut reactions: harnessing microbial metabolism to fuel next-generation cancer immunotherapy.
    Andrew A Almonte, Laurence Zitvogel.
      Immunotherapies, including immune checkpoint inhibitors and chimeric antigen receptor-T cell therapies, depend heavily on a healthy and diverse gut microbiome for optimal efficacy. Dysbiosis, or an imbalance in gut microbial composition and function, can diminish immunotherapy responses by altering immune cell trafficking and metabolic output. Key microbial metabolites such as short-chain fatty acids and modified bile acids shape host immunity and influence T-cell function, while their disruption can foster an immunosuppressive microenvironment. Emerging strategies to restore a balanced microbiome and boost treatment outcomes include dietary interventions, supplementation with beneficial microbes, and fecal microbiota transplantation. Despite these advances, challenges remain in defining dysbiosis, identifying reliable biomarkers, and tailoring microbiota-centered interventions. Nevertheless, as our understanding evolves, the gut microbiome holds promise as an integral component of personalized cancer immunotherapy.
    Keywords:  Biomarker; Immune modulatory; Immunotherapy
    DOI:  https://doi.org/10.1136/jitc-2025-011540
  20. Sci Rep. 2025 May 01. 15(1): 15314
    Single-cell sequencing combined with bulk RNA seq reveals the roles of natural killer cell in prognosis and immunotherapy of hepatocellular carcinoma.
    Jiahao Wu, Fan Yang, Guanqun Huang.
      Hepatocellular carcinoma (HCC) is a type of highly heterogeneous tumor characterized by a high mortality rate and poor prognosis. Natural Killer cells (NK cells) are important immune cells that play an important role in anti-tumor activities, antiviral responses, and immune regulation. The relationship between NK cells and HCC remains unclear. It would be valuable to identify a NK-related prognostic signature for HCC. WGCNA and single-cell sequencing RNA were performed to identify NK cell related genes. Gene Enrichment Analysis were used to identify the potential signal pathway. After combing genes from WGCNA and scRNA, Unicox, LASSO + StepCox and Multicox analysis were used to filter prognostic-related gene and construct a prognostic model. Then we performed Proposed time analysis to identify the developmental trajectories of NK cells. Finally, ssGSEA and estimate methods were used to evaluate the immune microenvironment and sensitivity drugs. Using the scRNA-seq data, we identified 1396 genes with high NK cell scores. Based on the results of scRNA-seq, 250 NK-related genes were identified from WGCNA. We identified 223 intersecting genes between the scRNA-seq and WGCNA. After integrating clinical data with the bulk RNA-seq data of these intersecting genes, we constructed a prognostic model to accurately predict the prognosis of HCC patients. Eventually, we found that high-risk HCC patients exhibited worse survival outcomes and lower sensitivity to immunotherapy. We constructed a risk model based on NK cell-related genes that can predict the prognosis of HCC patients accurately. This model can also predict the immunotherapy response of HCC effectively.
    Keywords:  Hepatocellular carcinoma; Immunotherapy; Natural killer cell; ScRNA; WCGNA
    DOI:  https://doi.org/10.1038/s41598-025-99638-w
  21. J Immunother Cancer. 2025 Apr 28. pii: e011522. [Epub ahead of print]13(4):
    Go to the scene: TH9 cells superior migration ability to the lungs explains their exceptional anticancer efficacy.
    Jiazhi Xu, Lionel Apetoh.
      Antibodies against immune checkpoints are now routinely administered as a first line of treatment against metastatic lung cancer. Resistance to immune checkpoint inhibitors is, however, frequent, underscoring the need to find alternative treatments. Adoptive T-cell therapy has recently proven effective in treating patient's refractory to immune checkpoint inhibitors. This provides impetus to characterize the T-cell subsets best able to tackle tumors. The anticancer activities of IL-9-producing CD4 T helper cells (TH9 cells) were identified in melanoma in 2012. TH9 cells feature strong antimelanoma effects thanks to their production of interleukin (IL)-9 and the activation of innate and adaptive immune effectors. The ability of TH9 cells to prevent the growth of triple-negative breast cancer (TNBC) and osteosarcoma (OS), which commonly metastasize to the lungs, is elusive. In this commentary, we discuss the findings of Chen et al reported in the JITC demonstrating that TH9 cells are lung-tropic and eliminate TNBC and OS cells developing in the lungs. We also highlight how these investigations are in line with recent studies indicating that the adoptive transfer of IL-9-producing T cells eliminate aggressive cancers, including hematological tumors like leukemia and solid tumors such as glioblastoma. Altogether, these findings over the past 13 years support the clinical evaluation of TH9 cells in the adoptive therapy of cancer.
    Keywords:  Adoptive cell therapy - ACT; Immune Checkpoint Inhibitor; T cell
    DOI:  https://doi.org/10.1136/jitc-2025-011522
  22. MedComm (2020). 2025 May;6(5): e70192
    Tissue Engineering and Regenerative Medicine: Perspectives and Challenges.
    Van T Hoang, Quyen Thi Nguyen, Trang Thi Kieu Phan, Trang H Pham, Nhung Thi Hong Dinh, Le Phuong Hoang Anh, Lan Thi Mai Dao, Van Dat Bui, Hong-Nhung Dao, Duc Son Le, Anh Thi Lan Ngo, Quang-Duong Le, Liem Nguyen Thanh.
      From the pioneering days of cell therapy to the achievement of bioprinting organs, tissue engineering, and regenerative medicine have seen tremendous technological advancements, offering solutions for restoring damaged tissues and organs. However, only a few products and technologies have received United States Food and Drug Administration approval. This review highlights significant progress in cell therapy, extracellular vesicle-based therapy, and tissue engineering. Hematopoietic stem cell transplantation is a powerful tool for treating many diseases, especially hematological malignancies. Mesenchymal stem cells have been extensively studied. The discovery of induced pluripotent stem cells has revolutionized disease modeling and regenerative applications, paving the way for personalized medicine. Gene therapy represents an innovative approach to the treatment of genetic disorders. Additionally, extracellular vesicle-based therapies have emerged as rising stars, offering promising solutions in diagnostics, cell-free therapeutics, drug delivery, and targeted therapy. Advances in tissue engineering enable complex tissue constructs, further transforming the field. Despite these advancements, many technical, ethical, and regulatory challenges remain. This review addresses the current bottlenecks, emphasizing novel technologies and interdisciplinary research to overcome these hurdles. Standardizing practices and conducting clinical trials will balance innovation and regulation, improving patient outcomes and quality of life.
    Keywords:  bioprinting; cell therapy; extracellular vesicle‐based therapy; regenerative medicine; stem cell; tissue engineering
    DOI:  https://doi.org/10.1002/mco2.70192
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