Experimental Hematology & Oncology最新文献

{"title":"Lactylation modification in cancer: mechanisms, functions, and therapeutic strategies.","authors":"Mengqi Lv, Yefei Huang, Yansu Chen, Kun Ding","doi":"10.1186/s40164-025-00622-x","DOIUrl":"10.1186/s40164-025-00622-x","url":null,"abstract":"<p><p>Cancer remains the leading cause of mortality worldwide, and the emergence of drug resistance has made the identification of new therapeutic targets imperative. Lactate, traditionally viewed as a byproduct of glycolysis with limited ATP-producing capacity, has recently gained recognition as a critical signaling molecule. It plays a key role not only in cancer cell metabolism but also in shaping the tumor microenvironment (TME). Histone lysine lactylation, a newly identified post-translational modification, has been shown to influence a range of cellular processes in cancer. Current research focuses on the mechanisms and functions of histone lactylation in cancer, including its role in gene expression regulation, signal transduction, and protein synthesis. However, despite these advancements, there are still plenty of barriers in the quest to unravel the mechanisms of lactylation modification. The emergence of single-cell and spatial transcriptomics may offer valuable insights for selecting targets. This review provides a comprehensive summary of the mechanisms and the applications of lactylation modification in clinical settings. Through a detailed analysis, we identify the key challenges and limitations that exist in the current research landscape. These insights lay the groundwork for future studies by highlighting promising research directions.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"32"},"PeriodicalIF":9.4,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11889934/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585223","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":"Bone marrow sympathetic neuropathy is a hallmark of hematopoietic malignancies and it involves severe ultrastructural damage.","authors":"Aurora Bernal, Vincent Cuminetti, Marc Serulla, Adrian Florit, Joanna Konieczny, Golnaz Golnarnik, Yimeng Chen, Marc Ferré, Samuel Geiseler, Anders Vik, Randi Olsen, Lorena Arranz","doi":"10.1186/s40164-025-00614-x","DOIUrl":"10.1186/s40164-025-00614-x","url":null,"abstract":"<p><p>The hematopoietic stem cell (HSC) niche in the bone marrow (BM) supports HSC function, fate and numbers [1]. Sympathetic fibres innervate the BM and are components of the hematopoietic stem and progenitor cell (HSPC) niche [2]. Neuropathy of the HSPC niche is present and essential for disease development in experimental models of JAK2^V617F+ myeloproliferative neoplasms (MPN) and MLL-AF9⁺ acute myeloid leukemia (AML), and it is present in the BM of human MPN and AML patients [3-6]. Neuropathy contributes to mutant HSC expansion and represents an effective therapeutic target to block disease progression in JAK2^V617F+ MPN mice [3]. The sympathomimetic agonist mirabegron restored nestin⁺ cells and reduced reticulin fibrosis in MPN patients [7]. Here, we show that neuropathy of the HSPC niche emerges in two additional experimental models of hematological disease including pre-leukemic myelopoiesis driven by NRAS^G12D and lymphoma/lymphoblastic leukemia driven by p53 deletion. Neuropathy involves severe ultrastructural damage in NRAS^G12D+ mice and AML patients as shown by electron microscopy. When further reinforced chemically, neuropathy has a profound impact on the experimental NRAS^G12D mouse model, promoting myeloid bias, reducing HSPC numbers and inducing changes in the stem cell microenvironment that include reduced numbers of mesenchymal stromal cells (MSC) and increased presence of morphologically abnormal blood vessels in BM. Together, BM neuropathy is a prevalent factor in hematopoietic malignancies that involves important degradation of sympathetic fibres and contributes to disease in a different manner depending on the driver mutation. This should be taken in consideration in the clinic, given that chemotherapy induces neuropathy of the HSC niche [8] and it is the most frequent first line treatment for AML, acute lymphoblastic leukemia and MPN patients.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"31"},"PeriodicalIF":9.4,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11884145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566526","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":"Matching-adjusted indirect comparison of efficacy and safety of lisocabtagene maraleucel and mosunetuzumab for the treatment of third-line or later relapsed or refractory follicular lymphoma.","authors":"Loretta J Nastoupil, Ashley Bonner, Pearl Wang, Lamees Almuallem, Jigar Desai, Thalia Farazi, Jinender Kumar, Saurabh Dahiya","doi":"10.1186/s40164-025-00610-1","DOIUrl":"10.1186/s40164-025-00610-1","url":null,"abstract":"<p><strong>Background: </strong>The treatment landscape for relapsed or refractory (R/R) follicular lymphoma (FL) has changed with the introduction of anti-CD19 chimeric antigen receptor T-cell therapies, including lisocabtagene maraleucel (liso-cel) and CD20 × CD3 bispecific T-cell-engaging monoclonal antibodies such as mosunetuzumab. Liso-cel and mosunetuzumab have demonstrated positive benefit-risk profiles for third-line or later (3L+) treatment of patients with R/R FL and are approved treatments for these patients. In the absence of a prospective, randomized study, we conducted an unanchored matching-adjusted indirect comparison (MAIC) to assess the efficacy and safety of liso-cel and mosunetuzumab for 3L+ treatment in patients with R/R FL.</p><p><strong>Methods: </strong>Unanchored MAICs were performed to estimate relative treatment effects between TRANSCEND FL (NCT04245839) and GO29781 (NCT02500407). For TRANSCEND FL, the leukapheresis set (N = 114) was used for primary comparisons of the following efficacy endpoints: objective response rate (ORR), complete response (CR) rate, duration of response (DOR), and progression-free survival (PFS). The treated set (N = 107) was used for comparisons of the following safety endpoints: cytokine release syndrome (CRS), neurological events (NE), serious infections, and use of corticosteroids or tocilizumab for CRS. Sensitivity analyses were conducted for efficacy using the TRANSCEND FL treated efficacy set (N = 101).</p><p><strong>Results: </strong>After adjustment, liso-cel was associated with higher ORR (odds ratio [OR] = 3.78, 95% confidence interval [CI] 1.48‒9.67]) and CR rate (OR = 6.46, 95% CI 2.85‒14.65), and improved DOR (hazard ratio [HR] = 0.45, 95% CI 0.26‒0.77) and PFS (HR = 0.28, 95% CI 0.16‒0.49) compared with mosunetuzumab. Results remained consistent across sensitivity analyses. Liso-cel had a lower incidence of grade ≥ 3 CRS (OR = 0.45, 95% CI 0.04‒5.13), grade 3‒4 serious infections (OR = 0.35, 95% CI 0.12‒1.03), and corticosteroid use for CRS management (OR = 0.14, 95% CI 0.03‒0.65); however, liso-cel exhibited higher incidence of any-grade CRS (OR = 1.86, 95% CI 1.01‒3.43), any-grade NEs (OR = 2.16, 95% CI 0.72‒6.44), and tocilizumab use for CRS management (OR = 2.27, 95% CI 0.86‒5.99).</p><p><strong>Conclusions: </strong>Findings highlight a potential positive benefit-risk profile of liso-cel over mosunetuzumab as a 3L+ treatment for R/R FL.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"30"},"PeriodicalIF":9.4,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566531","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":"Ibrutinib and acalabrutinib use and risk of incident atrial fibrillation: a propensity-matched analysis.","authors":"Joachim Alexandre, Jonaz Font, Thibault Lenormand, Sylvain Chantepie, Hippolyte Bardet, Gandhi Damaj, Charles Dolladille, Damien Legallois, Angélique Da-Silva, Paul Milliez, Arnaud Bisson, Laurent Fauchier","doi":"10.1186/s40164-025-00619-6","DOIUrl":"10.1186/s40164-025-00619-6","url":null,"abstract":"<p><p>Ibrutinib and acalabrutinib are both associated with an increased risk of atrial fibrillation (AF); however, the comparative risk of AF between these 2 BTK inhibitors remains largely unknown. Our primary aim was to evaluate the risk of incident AF in patients exposed to ibrutinib compared to those exposed to acalabrutinib. Using the TriNetX research network database, we established a retrospective cohort of adult patients (≥ 18 years) previously diagnosed with a B-cell malignancy (using ICD-10-CM codes) in whom a first BTKi introduction occurred between January 1st, 2013 (first patient exposed to ibrutinib in TriNetX) and July 1st, 2024. Patients were divided into 2 groups based on their exposure to ibrutinib or acalabrutinib. After propensity score matching (PSM) across 37 covariates, Cox proportional hazard models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) to compare the 2 matched groups. The appropriateness of the proportional hazard assumption was examined and risk differences (RDs) were used if appropriate. Results were summarized with the use of Kaplan-Meier survival curves. Follow-up started from 1 day after first BTKi introduction and continued over a 6-year follow-up period. A cohort of 12,449 patients exposed to ibrutinib and 4,131 to acalabrutinib were included in the study. After PSM, 4,090 patients remained in each group (1:1). During a mean duration of BTKi exposure of 2.3 ± 1.8 years, we found a significantly higher risk of incident AF in the ibrutinib group compared to the acalabrutinib group (RD 0.09, 95% CI 0.07-0.10). This difference was consistent across subgroups (age ≤ or > 75 and lower or higher baseline cardiovascular risk of developing AF). In conclusion, among patients with B-cell malignancies, the risk of developing incident AF is increased when treated with ibrutinib compared to acalabrutinib.Trial registration ClinicalTrial registration number: NCT06561243.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"29"},"PeriodicalIF":9.4,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556426","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":"Mesothelin-targeted CAR-T cells secreting NKG2D-BiTEs exhibit potent efficacy against triple-negative breast cancer.","authors":"Muhammad Auwal Saliu, Qi Wang, Mansur Dabai Salisu, Yuanfeng Ren, Pengchao Zhang, Rabiatu Bako Suleiman, Bingbing Cao, Yiqiao Xu, Xudong Liu, Frederic Lluis, Maoxuan Liu, Xiaochun Wan","doi":"10.1186/s40164-025-00621-y","DOIUrl":"10.1186/s40164-025-00621-y","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis and limited treatment options. Chimeric antigen receptor (CAR)-T cell therapy holds promise, but its efficacy is hindered by tumor antigen escape and heterogeneity. To address these challenges, we developed a novel bispecific T cell engagers CAR-T (BiTEs CAR-T) targeting Mesothelin (MSLN) and secreting NKG2D-Bispecific T cell Engagers (BiTEs) to engage NKG2D ligands (NKG2DL). Analysis of TNBC tissues using The Cancer Genome Atlas and tumor microarrays revealed high but weakly correlated expression of MSLN and NKG2DL, making them ideal targets for dual engagement. To reduce immunogenicity and enhance stability, we used a nanobody and the natural receptor NKG2D as antigen-binding domains instead of traditional scFvs in the CAR construct. The secreted BiTEs could promote the cytotoxicity of untransduced T cells against NKG2DL + tumor cells. In vitro, BiTEs CAR-T cells exhibited superior cytotoxicity, T cell activation, and cytokines production against heterogeneous target cells compared to MSLN CAR-T. In vivo, BiTEs CAR-T cells demonstrated potent antitumor activity in zebrafish and murine TNBC models, significantly reducing tumor burden and prolonging survival without detectable toxicity. These findings suggest that BiTE CAR-T cells offer a highly promising therapeutic strategy for TNBC by addressing antigen heterogeneity and immune escape mechanisms, with promising translational potential for clinical application.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"27"},"PeriodicalIF":9.4,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11874698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540816","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":"CD28 is superior to 4-1BB costimulation in generating CAR-NK cells for tumor immunotherapy.","authors":"Pengchao Zhang, Xuejia Feng, Xiangyun Niu, Zhongming Liu, Minghui Li, Maoxuan Liu, Dehong Yan, Guizhong Zhang, Xiaochun Wan","doi":"10.1186/s40164-025-00618-7","DOIUrl":"10.1186/s40164-025-00618-7","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR)-NK therapy holds great potential for tumor treatment, but current CAR designs are primarily optimized for T cells, raising concerns about their suitability for NK cells. This study compared two dominant CAR designs used in T cells-CD28-CD3ζ (28z) and 4-1BB-CD3ζ (BBz)-and found that CD28 costimulation offers superior functionality in NK cells. 28z CAR-NK cells exhibited significantly better activation, cytotoxicity, and in vivo anti-tumor efficacy than BBz CAR-NK cells, with similar persistence and tumor infiltration. 28z CAR more effectively recruited the ZAP70 kinase and upregulated multiple key factors involved in immune activation, potentially augmenting CAR-NK cell function. MAP3K8, a kinase involved in inflammation and the MAPK signaling pathway, was identified as a critical mediator in enhancing 28z CAR-NK cell function. Silencing or inhibiting MAP3K8 impaired the anti-tumor activity of 28z CAR-NK cells, while its overexpression substantially improved the function of BBz CAR-NK cells. These findings provide new insights into how CD28 costimulation boosts CAR-NK cell efficacy, supporting its use into NK cell-specific CARs for cancer immunotherapy, and highlight MAP3K8 as a potential target for optimizing BBz CAR-NK cell therapy.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"28"},"PeriodicalIF":9.4,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11874623/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540813","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":"IRF1 is a core transcriptional regulatory circuitry member promoting AML progression by regulating lipid metabolism.","authors":"Fenli Zhang, Zhiheng Li, Fang Fang, Yixin Hu, Zhixu He, Yanfang Tao, Yizhen Li, Zimu Zhang, Bi Zhou, Ying Yang, Yumeng Wu, Yijun Wu, Zhongling Wei, Ailian Guo, Ling Xu, Yongping Zhang, Xiaolu Li, Yan Li, Chunxia Yang, Man Zhou, Jian Pan, Shaoyan Hu, Xiaoyan Yang","doi":"10.1186/s40164-025-00612-z","DOIUrl":"10.1186/s40164-025-00612-z","url":null,"abstract":"<p><strong>Background: </strong>Acute myeloid leukemia (AML) is a prevalent malignancy of the hematologic system. Despite advancements in therapeutic approaches, significant heterogeneity and therapeutic resistance pose substantial challenges to treatment. Tumors driven by core transcription factors through super-enhancers can establish core transcriptional regulatory circuits (CRCs) that modulate oncogene expression programs. Identifying CRC is crucial for understanding disease-related transcriptional regulation. This study sought to predict and establish a CRC model for AML, identify genes critical for AML survival and explore their regulatory mechanisms in AML progression.</p><p><strong>Methods: </strong>The dbCoRC tool was used for predictive analysis of H3K27ac ChIP-seq data from 11 AML samples to construct and validate the CRC model in AML patients. To elucidate the functional role of the CRC member IRF1, we utilized short hairpin RNA (shRNA) to knock down IRF1 in AML cells. RNA-seq, CUT&Tag and lipidomics technologies were subsequently used to investigate the regulatory roles and downstream mechanisms of IRF1 in AML.</p><p><strong>Results: </strong>This study established a core transcriptional regulatory circuit consisting of IRF1, ELF1, ETV6, RUNX2, and MEF2D, which formed an interconnected autoregulatory loop. Further investigations revealed up-regulated expression of IRF1 in AML patients, which was associated with poor prognosis. Inhibition of IRF1 expression resulted in decreased AML cell proliferation and induced apoptosis, indicating its essential role in the survival of AML cells. Additionally, this study revealed that IRF1 directly regulates the transcription of key genes such as FASN, SCD, and SREBF1 for lipid synthesis, thereby affecting lipid metabolism in AML cells.</p><p><strong>Conclusion: </strong>In summary, this study identified IRF1 as a novel core transcription factor involved in AML pathogenesis. IRF1 collaborates with ELF1, ETV6, RUNX2, and MEF2D to form a core transcriptional regulatory circuit that promotes AML progression. Furthermore, we demonstrated that IRF1 directly regulates the expression of key genes involved in lipid metabolism, influencing the synthesis of diverse lipid molecules crucial for AML survival.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"25"},"PeriodicalIF":9.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11871635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536835","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":"Dickkopf-1 promotes tumor progression of gefitinib- resistant non-small cell lung cancer through cancer cell-fibroblast interactions.","authors":"Munkyung Choi, Yong June Choi, Young Joo Lee, Yujeong Lee, Jin-Haeng Chung, Keon Wook Kang","doi":"10.1186/s40164-025-00616-9","DOIUrl":"10.1186/s40164-025-00616-9","url":null,"abstract":"<p><strong>Background: </strong>Cancer cell-secreted proteins play a critical role in tumor progression and chemoresistance by influencing intercellular interactions within the tumor microenvironment. Investigating the intratumoral functions of these secretory proteins may provide insights into understanding and treating chemoresistant cancers. This study aims to identify potential anticancer target(s) in gefitinib-resistant non-small cell lung cancer (NSCLC), with a focus on secretory proteins and their effects on intercellular interactions.</p><p><strong>Methods: </strong>Differentially expressed secretory proteins were identified in gefitinib-resistant human NSCLC cell lines (PC9-GR and HCC827-GR), revealing an elevation in Dickkopf-1 (DKK1) expression and secretion. To elucidate the role of DKK1 in gefitinib-resistant cancer, the anticancer effects of a neutralizing antibody against DKK1 were evaluated in tumors comprising either cancer cells alone or cancer cells co-injected with human lung fibroblasts (MRC-5). Following the confirmation of the importance of cancer cell-fibroblast interactions in the protumorigenic activity of DKK1, the fibroblast traits modulated by DKK1 were further analyzed.</p><p><strong>Results: </strong>Gefitinib-resistant NSCLC cells exhibited increased DKK1 protein expression. Although elevated DKK1 levels were linked to poor prognosis, DKK1 did not directly affect cancer cell proliferation. However, DKK1 blockade showed significant anticancer effects in gefitinib-resistant tumors containing lung fibroblasts, suggesting that DKK1's pro-tumorigenic roles are mediated through cancer cell-fibroblast interactions. DKK1 altered fibroblast characteristics, enhancing inflammatory fibroblast traits while diminishing myofibroblast traits in tumor microenvironment. These DKK1-induced changes were mediated via activation of the c-JUN pathway in fibroblasts. Moreover, DKK1 was identified as a potential anticancer target across various cancer types beyond gefitinib-resistant lung cancer.</p><p><strong>Conclusions: </strong>This study clarifies that DKK1 mediates interactions between cancer cells and fibroblasts in gefitinib-resistant lung cancer, contributing to tumor progression. Therefore, we propose DKK1 as a promising anticancer target for the treatment of gefitinib-resistant NSCLC.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"24"},"PeriodicalIF":9.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11871833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536822","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":"TLR7/8 signaling activation enhances the potency of human pluripotent stem cell-derived eosinophils in cancer immunotherapy for solid tumors.","authors":"Sheng Zhu, Zhengyang Zhou, Ruixin Gu, Zixin Zhao, Yingfeng Zhang, Yudi Miao, Qi Lei, Tianxing Liu, Guokai Wang, Chenyi Dai, Yi Huo, Jinghao You, Lejun Lv, Cheng Li, Ming Yin, Chengyan Wang, Hongkui Deng","doi":"10.1186/s40164-025-00613-y","DOIUrl":"10.1186/s40164-025-00613-y","url":null,"abstract":"<p><strong>Background: </strong>Efficient tumor T-cell infiltration is crucial for the effectiveness of T-cell-based therapies against solid tumors. Eosinophils play crucial roles in recruiting T cells in solid tumors. Our group has previously generated induced eosinophils (iEOs) from human pluripotent stem cells and exhibited synergistic efficacy with CAR-T cells in solid tumor inhibition. However, administrated eosinophils might influx into inflammatory lungs, posing a potential safety risk. Mitigating the safety concern and enhancing efficacy is a promising development direction for further application of eosinophils.</p><p><strong>Methods: </strong>We developed a new approach to generate eosinophils with enhanced potency from human chemically reprogrammed induced pluripotent stem cells (hCiPSCs) with the Toll-like receptor (TLR) 7/8 signaling agonist R848.</p><p><strong>Results: </strong>R848-activated iEOs (R-iEOs) showed significantly decreased influx to the inflamed lungs, indicating a lower risk of causing airway disorders. Furthermore, these R-iEOs had enhanced anti-tumor functions, preferably accumulated at tumor sites, and further increased T-cell infiltration. The combination of R-iEOs and CAR-T cells suppressed tumor growth in mice. Moreover, the chemo-trafficking signaling increased in R-iEOs, which may contribute to the decreased lung influx of R-iEOs and the increased tumor recruitment of T cells.</p><p><strong>Conclusion: </strong>Our study provides a novel approach to alleviate the potential safety concerns associated with eosinophils while increasing T-cell infiltration in solid tumors. This finding offers a prospective strategy for incorporating eosinophils to improve CAR-T-cell immunotherapy for solid tumors in the future.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"26"},"PeriodicalIF":9.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11871822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536836","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":"TET2 downregulation enhances the antitumor efficacy of CD19 CAR T cells in a preclinical model.","authors":"Yeongrin Kim, Moonjung Jeun, Heung Kyoung Lee, Ji U Choi, Simon Park, Chi Hoon Park","doi":"10.1186/s40164-025-00609-8","DOIUrl":"10.1186/s40164-025-00609-8","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T cell therapy has demonstrated significant clinical efficacy in patients with hematologic cancers. However, long-term follow-up studies indicate that only 50% of patients remain in complete remission after three years. To overcome these limitations, we investigated a strategy to enhance the antitumor activity of CAR T cells through gene modification. Based on previous research results demonstrating that CAR T cells with disrupted TET2, a methylcytosine dioxygenase, exhibit enhanced antitumor effects compared to conventional CAR T, we developed CAR T cells in which TET2 is downregulated by TET2 shRNA. Among the screened TET2-specific shRNAs, TET2-shRNA-1 was identified as the most effective sequence for gene silencing. Using this sequence, we constructed an all-in-one vector co-expressing CD19 CAR and TET2 shRNA. In vitro studies demonstrated that TET2 knockdown CD19 CAR T cells exhibited comparable cytolytic activity against CD19-positive cancer cells compared to conventional CD19 CAR T cells. However, interestingly, in xenograft mouse model using NSG mice, TET2 knockdown CAR T cells showed significantly improved antitumor activity compared to conventional CAR T cells. Our study demonstrates that shRNA-mediated knockdown of TET2 is a promising strategy to enhance the antitumor activity of CD19 CAR T cells in a preclinical model.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"23"},"PeriodicalIF":9.4,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515202","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}