Experimental Hematology & Oncology最新文献

{"title":"Hypomethylating agents plus venetoclax for high-risk MDS and CMML as bridge therapy to transplant: a GESMD study.","authors":"Ines Zugasti, Monica Lopez-Guerra, Sandra Castaño-Díez, Daniel Esteban, Alejandro Avendaño, Helena Pomares, Ana Perez, Sara García-Ávila, Irene Padilla Conejo, Cristina de la Fuente Montes, Alexandra Martínez-Roca, Beatriz Merchán, Carlos Jiménez-Vicente, Francesca Guijarro, Jose Ramón Álamo, Albert Cortes-Bullich, Victor Torrecillas, Lucia Mont, Esther Carcelero, Gisela Riu, Lurdes Zamora, Joan Bargay, Ana Triguero, Maria Suarez-Lledó, Maria Queralt Salas, Felix López-Cadenas, Fernando Ramos, Blanca Xicoy, David Valcárcel, Montserrat Arnan, Carmen Martínez, Montserrat Rovira, Francesc Fernández-Avilés, Maria Díez-Campelo, Jordi Esteve, Marina Díaz-Beyá","doi":"10.1186/s40164-025-00652-5","DOIUrl":"https://doi.org/10.1186/s40164-025-00652-5","url":null,"abstract":"<p><strong>Background: </strong>High-risk myelodysplastic syndromes (HR-MDS) and chronic myelomonocytic leukemia (CMML) remain therapeutic challenges with suboptimal outcomes. The only potentially curative treatment is allogeneic stem cell transplantation (allo-SCT). The most frequent pre-allo-SCT treatment is monotherapy with hypomethylating agents (HMA), but approximately 40% of patients cannot proceed to allo-SCT, mainly due to disease progression. Recent evidence suggests that combining HMA with venetoclax (HMA/VEN) could increase HMA efficacy in HR-MDS but it remains unclear if this combination could bridge more patients to allo-SCT.</p><p><strong>Methods: </strong>We retrospectively evaluated HMA/VEN as a bridge to allo-SCT in 30 patients with HR-MDS or CMML eligible for transplant. Eighteen patients were treatment-naïve and 12 were refractory or relapsed (R/R).</p><p><strong>Results: </strong>As defined by the IWG 2023 criteria, the overall response rate (ORR) was 90% and the composite complete response rate was 77%. For the R/R patients, ORR was 83%. The allo-SCT rate was 83%, and the allo-SCT rate of those patients treated exclusively with HMA/VEN without further bridge therapies was 76%. One- and two-year post-allo-SCT survival was 75% and two-year cumulative incidence of relapse was 30.5%. Follow-up of measurable residual disease identified some molecular relapses that were controlled with preemptive treatment.</p><p><strong>Conclusions: </strong>Our findings indicate that HMA/VEN combination therapy shows promise as a bridging strategy to allo-SCT in HR-MDS and CMML.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"61"},"PeriodicalIF":9.4,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sarcosine sensitizes lung adenocarcinoma to chemotherapy by dual activation of ferroptosis via PDK4/PDHA1 signaling and NMDAR-mediated iron export.","authors":"Guangyao Shan, Yunyi Bian, Shencheng Ren, Zhengyang Hu, Binyang Pan, Dejun Zeng, Zhaolin Zheng, Hong Fan, Guoshu Bi, Guangyu Yao, Cheng Zhan","doi":"10.1186/s40164-025-00657-0","DOIUrl":"https://doi.org/10.1186/s40164-025-00657-0","url":null,"abstract":"<p><strong>Background: </strong>Ferroptosis, a regulated cell death driven by iron-dependent lipid peroxidation, is associated with chemoresistance in lung adenocarcinoma (LUAD). This study aims to investigate the role of sarcosine in ferroptosis and its underlying mechanisms.</p><p><strong>Methods: </strong>An RSL3-induced ferroptosis model was used to screen a library of 889 human endogenous metabolites and metabolomic profiling was harnessed to identify metabolites associated with ferroptosis. Cell viability, lipid-reactive oxygen species (ROS), ferrous iron, malondialdehyde (MDA), and mitochondrial integrity were assessed to evaluate sarcosine's effects on ferroptosis. Metabolic fate was studied using ¹⁵N-labeled sarcosine. Next, we used untargeted metabolomic profiling and next-generation sequencing to dissect metabolic and transcriptomic changes upon sarcosine supplementation. The effects of sarcosine on ferroptosis and chemotherapy were further validated in patient-derived organoids (PDOs), xenograft models, and LUAD tissues.</p><p><strong>Results: </strong>Sarcosine emerged as a potent ferroptosis inducer in the metabolic library screening, which was further confirmed via cell viability, lipid-ROS, ferrous iron, and MDA measurements. Metabolic flux analysis showed limited conversion of sarcosine to other metabolites in LUAD cells, while untargeted metabolomic profiling and seahorse assays indicated a metabolic shift from glycolysis to oxidative phosphorylation. Sarcosine enhanced pyruvate dehydrogenase activity to generate more ROS by interacting with PDK4, reducing PDHA1 phosphorylation. As a co-activator of N-methyl-D-aspartate receptor (NMDAR), sarcosine also exerted its pro-ferroptosis effect via regulating ferrous export through the NMDAR/MXD3/SLC40A1 axis. Given the significance of ferroptosis in chemotherapy, we validated that sarcosine enhanced the sensitization of cisplatin by promoting ferroptosis in LUAD cells, PDOs, and xenograft models.</p><p><strong>Conclusion: </strong>Sarcosine promotes ferroptosis and enhances chemosensitivity, suggesting its potential as a therapeutic agent in treating LUAD.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"60"},"PeriodicalIF":9.4,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12023509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143992912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-angiogenic tyrosine kinase inhibitors and the pathophysiology of their toxic effects: revisiting the treatment of anemia in metastatic cancers.","authors":"Tai Van Nguyen, Eurydice Angeli, Diaddin Hamdan, Morad El Bouchtaoui, Oanh T Bui, Feriel Azibani, Rong Shen, He Lu, Kien Hung Do, Anne Janin, Quang Van Le, Guilhem Bousquet","doi":"10.1186/s40164-025-00640-9","DOIUrl":"https://doi.org/10.1186/s40164-025-00640-9","url":null,"abstract":"<p><strong>Background: </strong>Anti-angiogenic tyrosine kinase inhibitors (TKIs) have become major drugs for the treatment of various cancer types, but with an overall high incidence of severe toxicities, particularly haematological toxicities including severe anemia.</p><p><strong>Methods: </strong>We treated C57BL6 mice continuously by gavage for 14 days with either sunitinib, pazopanib, or axitinib. In this study, we set out to decipher the pathophysiological mechanisms of anti-angiogenic TKI haematological toxicity.</p><p><strong>Results: </strong>We demonstrated that anti-angiogenic TKIs induced a broad range of toxic effects on normal tissues through a cytotoxic effect on normal endothelial cells. Haematological toxicities were particulary marked with sunitinib. Sunitinib-induced hypoxia through the destruction of normal vessels in the bone marrow mainly affected erythrocyte and myeloid lineages, and this was associated with a blockage in erythrocyte maturation. Althought sunitinib-induced anemia was associated with an adaptative response to systemic hypoxia, we demonstrated that erythropoietin (EPO) concentrations in the total bone marrow of sunitinib-treated mice were significantly lower than in untreated mice. This is coherent with the destruction of microvessels in the bone marrow under sunitinib treatment, preventing circulating EPO from reaching the bone marrow at relevant concentrations. However, we demonstrated an additional effect specific to sunitinib that induced autophagy flux inhibition in erythroid progenitors, with a blockage of erythrocyte maturation, leading to more severe anemia.</p><p><strong>Conclusions: </strong>We deciphered the pathophysiology of anti-angiogenic TKI-induced anemia, which we observed to be mainly linked to a direct effect on normal bone-marrow vessels and to autophagy flux inhibition in erythroid progenitors under sunitinib.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"59"},"PeriodicalIF":9.4,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12008949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Breakthroughs of CAR T-cell therapy in acute myeloid leukemia: updates from ASH 2024.","authors":"Haixiao Zhang, Hong-Hu Zhu","doi":"10.1186/s40164-025-00651-6","DOIUrl":"https://doi.org/10.1186/s40164-025-00651-6","url":null,"abstract":"<p><p>While chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape for lymphoid malignancies, its greatest challenge remains in the treatment of acute myeloid leukemia (AML). Its success in AML has been limited by the ideal target antigen, myelosuppression, and immunosuppressive leukemia microenvironment. The 2024 ASH Meeting highlighted several cutting-edge advancements in AML-directed CAR T therapies, including clinical trials targeting CD33, CD123, CLL1, CD19, and IL1RAP, as well as novel engineering strategies such as dual-targeting CARs, inhibitory CAR designs, and genome-editing approaches to enhance safety and efficacy. Here, we summarize key findings from both clinical and preclinical studies, offering insights into the evolving landscape of CAR T-cell therapy for AML.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"57"},"PeriodicalIF":9.4,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11987445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143992281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Validation of a microRNA profile in urine liquid biopsy with diagnostic and stratification value for bladder cancer classification, available through the open app BladdermiRaCan.","authors":"Julia Oto, Raquel Herranz, Emma Plana, Javier Pérez-Ardavín, David Hervás, Fernando Cana, Patricia Verger, David Ramos-Soler, Manuel Martínez-Sarmiento, César D Vera-Donoso, Pilar Medina","doi":"10.1186/s40164-025-00649-0","DOIUrl":"https://doi.org/10.1186/s40164-025-00649-0","url":null,"abstract":"<p><p>We aimed to identify a profile of urine microRNAs (miRNAs) with diagnostic and stratification potential in the whole range of bladder cancer (BC) categories, to avoid current invasive, harmful and expensive procedures. We collected a first morning urine sample from the screening (35 BC patients and 15 age- and gender-matched controls) and validation cohorts (172 BC and 94 controls). In the screening stage we analyzed the expression level of 179 miRNAs by real-time reverse transcription quantitative PCR in urine supernatants. miRNA levels in each sample were normalized by the levels of the previously identified and stably expressed miR-29c-3p. We performed an ordinal regression for each miRNA with False Discovery Rate (FDR) adjustment to identify dysregulated miRNAs, and an ordinal elastic net logistic regression model to identify a miRNA profile for BC diagnosis and stratification with the software R (v3.5.1). Next, we validated the most dysregulated miRNAs, and empirically identified the real miRNA targets in BC cells by miR-eCLIP immunoprecipitation and sequencing. We identified 70 dysregulated miRNAs in BC patients (p < 0.05 FDR-adjusted). With the expression level of 7 miRNAs in urine (miR-221-3p, miR-93-5p, miR-362-3p, miR-191-5p, miR-200c-3p, miR-192-5p, miR-21-5p) we could stratify BC patients and control subjects. To enable the global use of our model, we developed the free BladdermiRaCan online tool. Furthermore, we identified miR-21-5p, miR-425-5p and miR-99a-5p as follow-up markers for BC relapse, and miR-21-5p and miR-221-3p as markers for metastasis. These miRNAs were also dysregulated in BC tissue sections from a subgroup of patients from which urine samples were studied. In conclusion, we have validated and patented a 7-miRNAs urine profile able to diagnose and stratify BC patients; BladdermiRaCan will enable the global use of our model. The experimentally verified target proteins identified for these miRNAs may unravel novel therapeutic targets.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"58"},"PeriodicalIF":9.4,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11987439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144063134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: AOH1996 targets mitochondrial dynamics and metabolism in leukemic stem cells via mitochondrial PCNA inhibition.","authors":"HyunJun Kang, Melissa Valerio, Jia Feng, Long Gu, Dinh Hoa Hoang, Amanda Blackmon, Shawn Sharkas, Khyatiben Pathak, Jennifer Jossart, Zhuo Li, Hongyu Zhang, Bin Zhang, Patrick Pirrotte, J Jefferson P Perry, Robert J Hickey, Linda Malkas, Guido Marcucci, Le Xuan Truong Nguyen","doi":"10.1186/s40164-025-00650-7","DOIUrl":"https://doi.org/10.1186/s40164-025-00650-7","url":null,"abstract":"","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"56"},"PeriodicalIF":9.4,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11983855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunotherapy in chronic lymphocytic leukemia: advances and challenges.","authors":"Pan Gao, Yang Zhang, Jun Ma, Ya Zhang","doi":"10.1186/s40164-025-00644-5","DOIUrl":"https://doi.org/10.1186/s40164-025-00644-5","url":null,"abstract":"<p><p>Chronic lymphocytic leukemia (CLL) is characterized as a clonal proliferation of mature B lymphocytes with distinct immunophenotypic traits, predominantly affecting the middle-aged and elderly population. This condition is marked by an accumulation of lymphocytes within the peripheral blood, bone marrow, spleen, and lymph nodes. The associated immune dysregulation predisposes CLL patients to a higher risk of secondary malignancies and infections, which significantly contribute to morbidity and mortality rates. The advent of immunotherapy has revolutionized the prognosis of CLL, advancing treatment modalities and offering substantial benefits to patient outcomes. This review endeavors to synthesize and scrutinize the efficacy, merits, and limitations of the current immunotherapeutic strategies for CLL. The aim is to inform the selection of optimal treatment regimens tailored to individual patient needs. Furthermore, the review juxtaposes various therapeutic combinations to elucidate the comparative advantages of each approach, with the ultimate objective of enhancing patient prognosis and quality of life.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"53"},"PeriodicalIF":9.4,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11984025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular matrix stiffness: mechanisms in tumor progression and therapeutic potential in cancer.","authors":"Meiling Zhang, Bin Zhang","doi":"10.1186/s40164-025-00647-2","DOIUrl":"https://doi.org/10.1186/s40164-025-00647-2","url":null,"abstract":"<p><p>Tumor microenvironment (TME) is a complex ecosystem composed of both cellular and non-cellular components that surround tumor tissue. The extracellular matrix (ECM) is a key component of the TME, performing multiple essential functions by providing mechanical support, shaping the TME, regulating metabolism and signaling, and modulating immune responses, all of which profoundly influence cell behavior. The quantity and cross-linking status of stromal components are primary determinants of tissue stiffness. During tumor development, ECM stiffness not only serves as a barrier to hinder drug delivery but also promotes cancer progression by inducing mechanical stimulation that activates cell membrane receptors and mechanical sensors. Thus, a comprehensive understanding of how ECM stiffness regulates tumor progression is crucial for identifying potential therapeutic targets for cancer. This review examines the effects of ECM stiffness on tumor progression, encompassing proliferation, migration, metastasis, drug resistance, angiogenesis, epithelial-mesenchymal transition (EMT), immune evasion, stemness, metabolic reprogramming, and genomic stability. Finally, we explore therapeutic strategies that target ECM stiffness and their implications for tumor progression.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"54"},"PeriodicalIF":9.4,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11984264/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GLS2 inhibition synergizes with copper to reprogram TCA cycle for cuproptosis-driven radiosensitization in esophageal cancer.","authors":"Wang Jing, Wenhao Wang, Yi Ding, Renya Zeng, Hui Zhu, Zhichao Kang, Alei Feng, Zhe Yang","doi":"10.1186/s40164-025-00653-4","DOIUrl":"https://doi.org/10.1186/s40164-025-00653-4","url":null,"abstract":"<p><p>Esophageal squamous cell carcinoma (ESCC) is notorious for its poor prognosis. In the present study, the role of glutaminase 2 (GLS2) and copper (Cu) in the radiosensitivity of ESCC was explored. Both in vitro and in vivo experiments were conducted, and the results demonstrated that the knockdown of GLS2 could suppress cell proliferation and augment the sensitivity to radiotherapy (RT). The addition of Cu influenced cell viability and radiosensitivity. Notably, under normal GLS2 expression status, exogenous Cu augmented RT sensitivity without triggering cuproptosis. Mechanistically, the suppression of GLS2 interacted with Cu to downregulate lipoic acid synthase and dihydrolipoamide S-succinyltransferase, resulting in the reduction of the activity of α-ketoglutarate dehydrogenase complex and the obstruction of the tricarboxylic acid cycle, ultimately leading to the enhancement of RT sensitivity. These findings emphasize the significance of cuproptosis in ESCC radiotherapy and provide potential directions for therapeutic strategies.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"55"},"PeriodicalIF":9.4,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11983968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144000747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NKG2D/CD28 chimeric receptor boosts cytotoxicity and durability of CAR-T cells for solid and hematological tumors.","authors":"Xia Teng, Shance Li, Chaoting Zhang, Huirong Ding, Zhihua Tian, Yuge Zhu, Ting Liu, Guanyu Zhang, Kang Sun, Huimin Xie, Jiaxin Tu, Zheming Lu","doi":"10.1186/s40164-025-00646-3","DOIUrl":"10.1186/s40164-025-00646-3","url":null,"abstract":"<p><strong>Background: </strong>CAR-T cell therapy faces challenges in solid tumor treatment and hematologic malignancy relapse, among which the limited persistence of CAR-T cells and target antigen downregulation are prominent factors. Therefore, we engineered an NKG2D/CD28 chimeric co-stimulatory receptor (CCR), leveraging its broad ligand expression on tumors to enhance the antitumor activity of MSLN CAR and CD19 CAR-T cells.</p><p><strong>Methods: </strong>We generated MSLN CAR-T and CD19 CAR-T cells co-expressing the NKG2D/CD28 CCR and assessed their antitumor efficacy in vitro and in vivo. CAR-T cell activation, differentiation, and exhaustion were analyzed over time following tumor antigen stimulation. Furthermore, a chronic antigen stimulation model was established using tumor cells with low antigen density to simulate the sustained antigenic pressure encountered in vivo treatment conditions.</p><p><strong>Results: </strong>Our study shows that NKG2D/CD28&CAR-T cells exhibit enhanced cytotoxicity against tumor cells, especially those with low antigen density, both in vitro and in vivo. Compared to conventional second-generation MSLN CAR or CD19 CAR-T cells, these dual-targeted NKG2D/CD28&CAR-T cells demonstrate superior sensitivity in recognizing and lysing low-density antigen-expressing lung cancer and leukemia cells, and they are capable of eradicating tumors with low-density antigen expression in vivo. Furthermore, the complementary co-stimulation provided by the 4-1BB and CD28 intracellular domains in the CAR and NKG2D/CD28 promotes cytokine secretion, reduces CAR-T cell exhaustion, and enhances the in vivo persistence of CAR-T cells, significantly improving their antitumor efficacy.</p><p><strong>Conclusion: </strong>The combination of CAR and NKG2D/CD28 offers a potent strategy to enhance the cytotoxicity and durability of CAR-T cells. This approach is promising for improving therapeutic outcomes in solid and hematological tumors and preventing recurrence in tumors with low target antigen density.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"52"},"PeriodicalIF":9.4,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}