Experimental Hematology & Oncology最新文献

{"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":"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":"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":"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":"https://doi.org/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}

{"title":"The clinical landscape of CAR NK cells.","authors":"Lasse Vedel Jørgensen, Emil Birch Christensen, Mike Bogetofte Barnkob, Torben Barington","doi":"10.1186/s40164-025-00633-8","DOIUrl":"10.1186/s40164-025-00633-8","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) NK cell therapy has emerged as a promising alternative to CAR T cell therapy, offering significant advantages in terms of safety and versatility. Here we explore the current clinical landscape of CAR NK cells, and their application in hematologic malignancies and solid cancers, as well as their potential for treating autoimmune disorders. Our analysis draws from data collected from 120 clinical trials focused on CAR NK cells, and presents insights into the demographics and characteristics of these studies. We further outline the specific targets and diseases under investigation, along with the major cell sources, genetic modifications, combination strategies, preconditioning- and dosing regimens, and manufacturing strategies being utilized. Initial results from 16 of these clinical trials demonstrate promising efficacy of CAR NK cells, particularly in B cell malignancies, where response rates are comparable to those seen with CAR T cells but with lower rates of severe adverse effects, such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and graft-versus-host disease (GvHD). However, challenges remain in solid tumor applications, where only modest efficacy has been observed to date. Our analysis reveals that research is increasingly focused on enhancing CAR NK cell persistence, broadening their therapeutic targets, and refining manufacturing processes to improve accessibility and scalability. With recent advancements in NK cell engineering and their increased clinical applications, CAR NK cells are predicted to become an integral component of next-generation immunotherapies, not only for cancer but potentially for immune-mediated diseases as well.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"46"},"PeriodicalIF":9.4,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729376","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":"Hepatitis B surface antigen: carcinogenesis mechanisms and clinical implications in hepatocellular carcinoma.","authors":"Bingyan Hao, Yachong Liu, Bohan Wang, Haofeng Wu, Yan Chen, Lei Zhang","doi":"10.1186/s40164-025-00642-7","DOIUrl":"10.1186/s40164-025-00642-7","url":null,"abstract":"<p><p>Liver cancer is the third leading cause of death globally, with hepatitis B virus (HBV) infection being identified as the primary risk factor for its development. The occurrence of HBV-related hepatocellular carcinoma (HCC) is attributed to various mechanisms, such as chronic inflammation and liver cell regeneration induced by the cytotoxic immune response triggered by the virus, abnormal activation of oncogenes arising from HBV DNA insertion mutations, and epigenetic alterations mediated by viral oncoproteins. The envelope protein of the HBV virus, known as hepatitis B surface antigen (HBsAg), is a key indicator of increased risk for developing HCC in HBsAg-positive individuals. The HBsAg seroclearance status is found to be associated with recurrence in HCC patients undergoing hepatectomy. Additional evidence indicates that HBsAg is essential to the entire process of tumor development, from initiation to advancement, and acts as an oncoprotein involved in accelerating tumor progression. This review comprehensively analyzes the extensive effects and internal mechanisms of HBsAg during the various stages of the initiation and progression of HCC. Furthermore, it highlights the importance and potential applications of HBsAg in the realms of HCC early diagnosis and personalized therapeutic interventions. An in-depth understanding of the molecular mechanism of HBsAg in the occurrence and development of HCC is provided, which is expected to develop more precise and efficient strategies for the prevention and management of HCC in the future.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"44"},"PeriodicalIF":9.4,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718339","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":"Mechanisms of resistance to CAR-T cell therapy in multiple myeloma: latest updates from the 2024 ASH annual meeting.","authors":"Yuhan Hu, Jiangxue Hou, Zhongxing Jiang, Quande Lin","doi":"10.1186/s40164-025-00643-6","DOIUrl":"10.1186/s40164-025-00643-6","url":null,"abstract":"<p><p>Chimeric Antigen Receptor T-Cell (CAR-T) therapy demonstrates significant potential in the treatment of multiple myeloma (MM). However, resistance to CAR-T therapy remains a critical challenge. Investigating the mechanisms underlying CAR-T resistance, including antigen escape, immunosuppression, and CAR-T cell exhaustion, is essential for enhancing the long-term efficacy of this therapeutic approach. This study provides an in-depth review of the latest findings presented at the 66th ASH Annual Meeting.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"45"},"PeriodicalIF":9.4,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718342","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":"MMP14 from BM-MSCs facilitates progression and Ara-C resistance in acute myeloid leukemia via the JAK/STAT pathway.","authors":"Jinxian Wu, Xinqi Li, Yin Liu, Guopeng Chen, Ruihang Li, Hongqiang Jiang, Wanyue Yin, Xiqin Tong, Rui Cao, Xianwang Wang, Xiaoyan Liu, Fuling Zhou","doi":"10.1186/s40164-025-00635-6","DOIUrl":"10.1186/s40164-025-00635-6","url":null,"abstract":"<p><p>Growing evidence underscores the pivotal impact of crosstalk between leukemic stem cells (LSCs) and mesenchymal stromal cells (MSCs) within their niche on leukemia initiation, progression, and therapy response. Although MMP14 plays an important role in inflammation and cancer, the regulation and role of MSC-derived MMP14 in acute myeloid leukemia (AML) are largely unknown. Here, we found that AML patient-derived MSCs (AML-MSCs) were more supportive of AML cell growth compared to healthy donor-derived MSCs (HD-MSCs). Moreover, AML-MSCs and HD-MSCs showed significant differences in gene expression and protein expression profiles. Knockdown of MMP14 in MSCs inhibited the CFU-F ability of MSC cells and increased the proportion of cells in the G0 phase, thereby inhibiting proliferation. Co-culture with MSCs inhibited the proliferation and cell cycle progression of leukemia cells, while increasing the apoptosis rate, thus impairing the leukemogenic potential of AML cells both in vitro and in vivo. Mechanistic studies revealed that MMP14-mediated alterations in the AML stromal microenvironment are driven by PGE2 secretion and activation of the JAK-STAT pathway, promoting leukemia progression. Notably, inhibition of MMP14 can attenuate the chemotherapy resistance of AML cells induced by MSCs to cytarabine (Ara-C). Together, our study, for the first time, demonstrates the critical role of MSC-derived MMP14 in promoting AML progression and chemoresistance. Targeting MMP14 signaling pathways may offer novel therapeutic options for AML.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"43"},"PeriodicalIF":9.4,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11929205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691426","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}