Experimental Hematology & Oncology最新文献

{"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}

{"title":"Correction: Targeting and cytotoxicity of chimeric antigen receptor T cells grafted with PD1 extramembrane domain.","authors":"Ang Zhang, Shenyu Wang, Yao Sun, Yikun Zhang, Long Zhao, Yang Yang, Yijian Zhang, Lei Xu, Yangyang Lei, Jie Du, Hu Chen, Lian Duan, Mingyi He, Lintao Shi, Lei Liu, Quanjun Wang, Liangding Hu, Bin Zhang","doi":"10.1186/s40164-025-00645-4","DOIUrl":"10.1186/s40164-025-00645-4","url":null,"abstract":"","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"50"},"PeriodicalIF":9.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966879/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771087","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":"Interleukin-21 engineering enhances CD19-specific CAR-NK cell activity against B-cell lymphoma via enriched metabolic pathways.","authors":"Bailin He, Hong Chen, Jiaxu Wu, Shiqiu Qiu, Qiusui Mai, Qing Zeng, Cong Wang, Shikai Deng, Zihong Cai, Xiaoli Liu, Li Xuan, Chengyao Li, Hongsheng Zhou, Qifa Liu, Na Xu","doi":"10.1186/s40164-025-00639-2","DOIUrl":"10.1186/s40164-025-00639-2","url":null,"abstract":"<p><strong>Background: </strong>NK cells engineered to express interleukin-15 (IL-15) and a CD19-targeted chimeric antigen receptor (CAR) have been used to treat patients with relapsed and/or refractory B cell malignances, demonstrating encouraging outcomes and favorable safety profile. However, the effect of IL-21 in CAR-NK cell therapy remains unknown.</p><p><strong>Methods: </strong>CD19-specific CAR with 4-1BB costimulatory domain and cytokine IL-21 or IL-15 was constructed and transduced into peripheral blood (PB)-derived NK cells to produce CD19-CAR-IL21 NK cells (CAR-21) or CD19-CAR-IL15 NK cells (CAR-15), respectively. The phenotypic profile, transcriptomic characteristics, functionality and anti-tumor activity of CAR-21 NK cells and CAR-15 NK cells were compared.</p><p><strong>Results: </strong>Compared with CAR-NK cells co-expressing IL-15, CAR-NK cells co-expressing IL-21 exhibited significantly increased IFN-γ, TNF-α and Granzyme B production, as well as degranulation, in response to CD19⁺ Raji lymphoma cells, resulting in enhanced cytotoxic activity upon repetitive tumor stimulation. Furthermore, IL-21 co-expression improved the in vivo persistence of CAR-NK cells and significantly suppressed tumor growth in a xenograft Raji lymphoma murine model, leading to prolonged survival of CD19⁺ tumor-bearing mice. RNA sequencing revealed that CAR-21 NK cells have a distinct transcriptomic signature characterized by enriched in cytokine, cytotoxicity, and metabolic related signaling, when compared with CAR-15 NK or CAR NK cells.</p><p><strong>Conclusions: </strong>This study demonstrated that CD19-specific CAR-NK cells engineered to express IL-21 exhibit superior persistence and anti-tumor activity against CD19⁺ tumor compared to CAR-NK cells co-expressing IL-15, which might be a promising therapeutic strategy for treating patients with relapse or refractory B cell malignances.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"51"},"PeriodicalIF":9.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771577","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":"Siltuximab for the treatment of early complications after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia in children, adolescents, and young adults.","authors":"Víctor Galán-Gómez, Berta González-Martínez, Anna Alonso-Saladrigues, Susana Rives, Blanca Herrero, Mi Kwon, Jose Sánchez-Pina, Jordi Minguillón, Isabel Martínez-Romera, Isabel Mirones Aguilar, Carmen Mestre-Durán, Gema Casado, María Sánchez-Martín, Carlos Echecopar, Carlos González-Pérez, Odelaisy León-Triana, Cristina Aguirre-Portolés, Águeda Molinos-Quintana, Pere Barba, Pascual Balsalobre, Antonio Pérez-Martínez","doi":"10.1186/s40164-025-00638-3","DOIUrl":"10.1186/s40164-025-00638-3","url":null,"abstract":"<p><strong>Background: </strong>Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are complications associated with CAR T-cell therapy. Siltuximab directly binds interleukin-6 (IL-6) and may be safe and effective as first-line therapy for CRS or ICANS.</p><p><strong>Methods: </strong>A retrospective study was conducted on pediatric, adolescent and young adult (AYA) patients treated with siltuximab after CAR T-cell therapy for B-ALL.</p><p><strong>Results: </strong>A total of 118 patients treated were included: 97 patients developed CRS (82%), and 26 patients (22%) developed ICANS. Sixty-five of those that developed CRS (55%), received treatment. In 46/65 (71%), tocilizumab was administered as anti-IL-6 drug, and 19/65 (29%) patients received siltuximab to treat tocilizumab-refractory CRS (n = 13, 68%), or as first-line CRS treatment (n = 6, 32%). Nine patients treated with siltuximab (47%) developed ICANS. With a median follow-up of 12.1 months, 7 patients remained alive.</p><p><strong>Conclusions: </strong>To the best of our knowledge, we present the largest reported cohort of patients treated with siltuximab for CRS following CAR T-cell therapy for B-ALL. Siltuximab's safety profile and its inhibition of IL-6 effects suggest that it should be investigated as first-line therapy in prospective clinical trials.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"49"},"PeriodicalIF":9.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963303/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771617","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":"RNA modifications in the tumor microenvironment: insights into the cancer-immunity cycle and beyond.","authors":"You-Peng Ding, Cui-Cui Liu, Ke-Da Yu","doi":"10.1186/s40164-025-00648-1","DOIUrl":"10.1186/s40164-025-00648-1","url":null,"abstract":"<p><p>The chemical modification of biological molecules is a critical regulatory mechanism for controlling molecular functions. Although research has long focused on DNA and proteins, RNA modifications have recently attracted substantial interest with the advancement in detection technologies. In oncology, many studies have identified dysregulated RNA modifications including m6A, m1A, m5C, m7G, pseudouridylation and A to I editing, leading to disrupted downstream pathways. As the concept of the tumor microenvironment has gained prominence, studies have increasingly examined the role of RNA modifications in this context, focusing on interactions among cancer cells, immune cells, stromal cells, and other components. Here we review the RNA modifications in the tumor microenvironment through the perspective of the Cancer-Immunity Cycle. The extracellular RNA modifications including exosomes and influence of microbiome in RNA modifications are potential research questions. Additionally, RNA modifying enzymes including FTO, ALKBH5, METTL3, PUS7 are under investigation as potential biomarkers and targets for combination with immunotherapies. ADCs and mimetics of modified RNA could be potential novel drugs. This review discusses the regulatory roles of RNA modifications within the tumor microenvironment.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"48"},"PeriodicalIF":9.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771611","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":"A one-base therapeutic insertion in the HBG2 distal promoter reactivates γ-globin expression.","authors":"Xiuqin Bao, Yuanyi Gao, Xiaoyi Chen, Zhongju Wang, Xiaoqin Feng, Liren Wang, Jing Du, Yuhua Ye, Feijing Chen, Li Du, Aihua Yin, Xiangmin Xu","doi":"10.1186/s40164-025-00626-7","DOIUrl":"10.1186/s40164-025-00626-7","url":null,"abstract":"<p><strong>Background: </strong>The reactivation of developmental silenced γ-globin genes (HBG1/2) has shown promise as a therapeutic strategy for improving symptoms of β-hemoglobinopathies. Currently, the focus of therapeutic targets is primarily on the major fetal hemoglobin suppressors, such as BCL11A and ZBTB7A and of their binding sites on the proximal HBG promoter. However, the role of the distal HBG promoter in regulating gene expression remains to be explored.</p><p><strong>Methods: </strong>We used CRISPR/Cas9 system to edit the distal HBG promoter. In vitro and in vivo assays, as well as engrafted NCG-Kit-V831M mice, were used for functional validation and mechanistic studies.</p><p><strong>Results: </strong>We discovered an insertion of nucleotide A (insA) between - 1368 and - 1369 bp upstream of the TSS in HBG2 resulting in remarkable increase in γ-globin expression in HUDEP-2 cells. We also observed elevated γ-globin expression in human CD34⁺ erythroid progenitor cells from healthy individuals and those with β-thalassemia when introducing insA mutation. Similarly, engrafted NCG-Kit-V831M mice showed increased γ-globin expression. Importantly, neither did insA have any off-target effects nor did it affect the maturation of erythroid cells. Furthermore, we found that the insA mutation created a binding site for the transcription activator FOXO3, which was activated by AMPK. Additionally, introducing insA specifically demethylated the - 162 CpG site on HBG promoter by reducing the enrichment of DNA methyltransferase 3 A (DNMT3A). At the same time, it activated histone modifications and RNA polymerase II (Pol II) in both distal and proximal HBG promoter and might inhibit the binding of BCL11A and ZBTB7A on -115 and - 200 sites on the HBG promoter respectively. In addition, combination of insA and the - 115 or -200 editing targets resulted in an amplify effect in reactivating γ-globin genes expression.</p><p><strong>Conclusions: </strong>Overall, we presented the preclinical data to support the role of insA on regulating γ-globin expression using CD34⁺ HSPC cells derived from healthy donors or patients with β-thalassemia, and subsequently engrafted mice. Our study suggests that introducing insA mutation leads to significantly boosted fetal globin levels and uncovers new safe therapeutic target or strategy for β-hemoglobinopathies.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"47"},"PeriodicalIF":9.4,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951516/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742610","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}