Experimental Hematology & Oncology最新文献

{"title":"Extracellular matrix stiffness reduces DNA 6 ma level to facilitate colorectal cancer progression via disrupting P53 binding to CDKN1A promoter.","authors":"Si-An Xie, Xue Li, Min-Yue Yin, Feng Du, Shu-Tian Zhang, Sheng-Tao Zhu","doi":"10.1186/s40164-025-00704-w","DOIUrl":"10.1186/s40164-025-00704-w","url":null,"abstract":"<p><p>The extracellular matrix (ECM) forms the primary scaffold of the tumor microenvironment, with matrix stiffness serving as a critical physical cue that modulates cancer progression. However, the impact of matrix stiffness on colorectal cancer (CRC) progression remains elusive. This study aimed to elucidate the role of substrate stiffness in regulating DNA N6-methyladenine (6 mA) modifications and their association with CRC progression. We observed significantly reduced DNA 6 mA levels in CRC cells and tissues compared to normal controls, which progressively declined with advancing CRC stages. A negative correlation was identified between CRC tissue stiffness and DNA 6 mA levels. The 6 mA demethylase ALKBH1 was identified as a poor prognostic indicator in CRC and responded to increased substrate stiffness, correlating with enhanced CRC proliferation. Mechanistically, ALKBH1 mediated DNA 6 mA demethylation in response to substrate stiffening, thereby modulating gene transcription and promoting CRC tumorigenesis. Notably, ALKBH1 lost its proliferative effect in P53-knockout CRC cells, while a catalytically inactive ALKBH1 mutant suppressed oncogenesis. Furthermore, ALKBH1 diminished CDKN1A expression by impairing P53 binding to the CDKN1A promoter region. Collectively, our findings demonstrate that ALKBH1 acts as a pivotal mediator linking matrix stiffness to DNA 6 mA demethylation, critically driving CRC progression and highlighting its therapeutic potential. These results underscore the importance of DNA 6 mA modifications in CRC development and tumor response to microenvironmental cues.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"111"},"PeriodicalIF":13.5,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12382035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144947597","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":"Improving CAR-T cell function through a targeted cytokine delivery system utilizing car target-modified extracellular vesicles.","authors":"Yuanyuan Zhang, Meijuan Huang, Shujia Zhang, Tianjiao Liu, Shanwei Ye, Yuhang Cheng, Yang Cao, Liting Chen, Li Zhu, Xueyan Sun, Kefeng Shen, Qian Xu, Tongjuan Li, Dengju Li, Liang Huang, Wei Mu, Lei Zhao, Jue Wang","doi":"10.1186/s40164-025-00701-z","DOIUrl":"10.1186/s40164-025-00701-z","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR)-T-cell therapy has achieved remarkable clinical success in the treatment of B-cell malignancies; however, its efficacy can be limited by poor T-cell persistence and insufficient antitumor activity in certain cases. Moreover, interleukin-12 (IL-12) is a prominent agent in cancer immunotherapy, but its clinical application is constrained by severe toxicity associated with systemic exposure. In this study, we developed a novel cytokine delivery platform based on CAR target-modified cell-derived extracellular vesicles (EVs) that preferentially bind CAR-T cells to improve CAR-T-cell function. EVs with surface-displayed CD19 and/or IL-12 were successfully generated from HEK-293T cells. Compared with an equivalent concentration of rhIL-12, IL-12 EVs significantly enhanced the effector function of anti-CD19 CAR-T cells in vitro, resulting in increased Interferon-γ (IFN-γ) and TNF-α secretion, cytolytic activity, and T-cell expansion. Additionally, compared with EVs expressing IL-12 alone, EVs co-expressing IL-12 and CD19 (CD19/IL-12 EVs) exhibited superior binding efficiency to CAR-T cells but not to T cells, as indicated by flow cytometry. In xenograft model mice bearing CD19 + Raji tumors, intratumoral injection of CD19/IL-12 EVs resulted in durable antitumor responses and enhanced the in vivo expansion of CAR-T cells, outperforming CD19 EVs, IL-12 EVs and control EVs, without causing systemic toxicity. RNA sequencing (RNA-seq) analysis of CAR-T cells stimulated with EVs suggested that the increased efficacy was driven by IL-12 signaling. These data demonstrate that CAR-targeted modified EVs may serve as targeted cytokine delivery systems for CAR-T cells, offering a safe and effective strategy to augment CAR-T-cell function.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"110"},"PeriodicalIF":13.5,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12379361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144947972","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":"Healing of lytic lesions and restoration of bone health in multiple myeloma through sclerostin inhibition.","authors":"Hayley M Sabol, Aric Anloague, Japneet Kaur, Cecile Bustamante-Gomez, Sharmin Khan, Bethany C Paxton, Mattie R Nester, Jillian Hackney, Marta Diaz-delCastillo, Daniel Mann, Jeffrey B Stambough, C Lowry Barnes, Elena Ambrogini, Alison Frontier, Frank H Ebetino, Syed Naqvi, Frits van Rhee, Christopher P Wardell, Matthew T Drake, Intawat Nookaew, Carolina Schinke, Maurizio Zangari, Jesus Delgado-Calle","doi":"10.1186/s40164-025-00699-4","DOIUrl":"10.1186/s40164-025-00699-4","url":null,"abstract":"<p><strong>Background: </strong>Multiple myeloma (MM) is associated with a debilitating bone disease that poses significant therapeutic challenges. MM bone disease is characterized by increased bone resorption and suppression of osteoblasts, which hinders the repair of damaged bone. Sclerostin, an antagonist of Wnt signaling, is elevated in MM patients, and its inhibition with a neutralizing antibody (Scl-ab) has been shown to restore osteoblast function in mouse models of MM. However, it remains unclear whether Scl-ab can promote skeletal repair, enable effective tumor control when combined with anti-cancer agents, or improve bone health in MM patients.</p><p><strong>Methods: </strong>To investigate these knowledge gaps, we used preclinical MM mouse models and patient-derived samples. We also characterize the impact of Scl-ab on cancer and osteoblastic cells isolated from mouse models through bulk and single-cell RNA sequencing. Lastly, we performed a retrospective analysis of the efficacy of Scl-ab to improve bone health in patients with MM in remission.</p><p><strong>Results: </strong>Scl-ab promoted skeletal repair and enabled tumor suppression by an anti-cancer agent in various animal models of established MM bone disease. MM tumors suppressed Wnt signaling and decreased the number of osteoblasts and osteo-CAR cells, and treatment with Scl-ab reversed these effects. Treatment with Scl-ab increased bone mass and repaired bone in patients with MM in remission, even when combined with maintenance chemotherapy.</p><p><strong>Conclusions: </strong>Our findings highlight the potent bone-healing effects of Scl-ab and its potential as an adjuvant to anti-cancer therapy, offering a promising approach to improve clinical outcomes and the quality of life for MM patients.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"108"},"PeriodicalIF":13.5,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12372396/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144947959","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 anticancer thiosemicarbazone triapine exerts immune-enhancing activities via immunogenic cell death induction and FAS upregulation.","authors":"Bianca Stiller, Alessia Stefanelli, Hemma Schueffl, Marlene Mathuber, Nadiya Skorokhyd, Judith Gufler, Christine Pirker, Martin Holcmann, Rostyslav Panchuk, Maria Sibilia, Doris Marko, Walter Berger, Christian R Kowol, Sonja Hager, Petra Heffeter","doi":"10.1186/s40164-025-00700-0","DOIUrl":"10.1186/s40164-025-00700-0","url":null,"abstract":"<p><p>The anticancer thiosemicarbazone Triapine is currently in a phase III clinical trial in combination with radiation therapy and cisplatin. Noteworthy, while radiotherapy induces an immune-activating cell death, so called immunogenic cell death (ICD), cisplatin possesses immunomodulatory and ICD-enhancing functions. Interestingly, although there are several indications that suggest that Triapine could also enhance the immune recognition of cancer cells, no investigations in this direction have been reported so far. Indeed, immune cells (especially cytotoxic T-cells) were found to enhance the anticancer activity of Triapine. This effect might be based on endoplasmic reticulum (ER) stress induction, which on the one hand led to ICD of the cancer cells as indicated by ATP release, calreticulin exposure, high-mobility group box 1 secretion and in vivo vaccination experiments. On the other hand, the Triapine-induced ER stress resulted in FAS upregulation in cell culture as well as in vivo via NFκB signaling. This, in turn, rendered cancer cells more susceptible to FASL (predominantly expressed by lymphoid immune cells)-induced caspase 8-mediated apoptosis. Consequently, our study is the first to unveil the significant role of the (adaptive) immune system in the anticancer activity of Triapine, positioning it as a promising partner for combination with immunotherapy and other immunogenic agents.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"109"},"PeriodicalIF":13.5,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12372321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144948047","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":"CD47 antibody-armed oncolytic adenovirus promotes chimeric antigen receptor macrophage phagocytosis and antitumor immunity.","authors":"Zhongbing Qi, Shichuan Hu, Jing Zhao, Xianglin Xu, Anliang Huang, Yu Qin, Yao Zhang, Qingzhe Yang, Jianchuan Hu, Chao Su, Ping Cheng","doi":"10.1186/s40164-025-00696-7","DOIUrl":"10.1186/s40164-025-00696-7","url":null,"abstract":"<p><strong>Background: </strong>Chimeric antigen receptor (CAR)-T cell therapy has shown success in hematologic malignancies but has encountered challenges in solid tumors. Macrophages, being a potentially effective therapeutic target, have led to the development of several therapeutic strategies due to their unique phagocytic function. This study aimed to develop an effective solid tumor immunotherapy strategy by combining CAR macrophages (CAR-Ms) targeting PD-L1 with CD47 antibody-armed oncolytic adenovirus (oAd-CD47).</p><p><strong>Methods: </strong>In this study, an adenoviral vector was employed to construct CAR-Ms that target PD-L1 and express IFN-γ. The phagocytic capacity and phenotype of CAR-Ms were tested in vitro. Two mouse tumor models with different immunogenicity were utilized to investigate the anti-tumor efficacy of CAR-Ms in vivo. Subsequently, the synergistic anti-tumor effects of CAR-M and oAd-CD47 and their underlying mechanisms were explored.</p><p><strong>Results: </strong>CAR-Ms exhibited enhanced phagocytic capacity and proinflammatory (M1) phenotype. These CAR-Ms significantly reduced tumor burden and extended overall survival in mice bearing CT26 colon cancer, a model characterized by high immunogenicity. Compared with CAR-Ms and oAd-CD47 monotherapy, this combination therapy (C + o) achieved superior antitumor efficacy in the CT26 and B16 melanoma mouse models, as well as in the ID8 peritoneal metastasis model. Notably, C + o treatment enhanced tumor-associated macrophage (TAM) phagocytosis and reduced the population of inhibitory immune cell subsets, thereby resulting in enhanced adaptive antitumor T-cell and neoantigen-specific T-cell immunity. Additionally, the synergistic antitumor effect of C + o was dependent on CD8⁺ T cells.</p><p><strong>Conclusion: </strong>The treatment strategy of CAR-Ms combined with oAd-CD47 provides a promising, novel and effective treatment method for individualized targeted therapy of solid tumors.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"106"},"PeriodicalIF":13.5,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355751/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854980","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":"Elevated TIM3 expression on bone marrow T cells drives immune dysfunction in early relapsed blood cancer after allogeneic hematopoietic stem cell transplantation.","authors":"Thi Thuy Duong Pham, Su-Young Choi, Jeong Suk Koh, Bu-Yeon Heo, Sang-Woo Lee, Myung-Won Lee, Wonhyoung Seo, Yunseon Jang, Jung-Hyun Park, Deog-Yeon Jo, Seungyeul Yoo, Jaeyul Kwon, Ik-Chan Song","doi":"10.1186/s40164-025-00697-6","DOIUrl":"10.1186/s40164-025-00697-6","url":null,"abstract":"<p><p>Relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the leading cause of treatment failure in patients with hematologic malignancies. To better understand the mechanisms underlying early relapse (ER), we comprehensively explored the expression of inhibitory receptors (IRs) in bone marrow (BM) T cells at differentiation stage and examined transcriptional differences. Among the evaluated IRs, TIM3 was significantly upregulated in CD3⁺T cells of patients with ER compared to patients with complete remission (CR). Notably, double-negative T (DNT) cells, a unique subset with MHC-independent cytotoxic potential, constituted a high proportion of BM T cells and expressed increased TIM3 expression in ER patients. Moreover, regulatory T cells (Tregs) showed elevated TIM3 levels, contributing to an immunosuppressive microenvironment after allo-HSCT. Transcriptomic analysis revealed downregulation of cytotoxic granules and effector genes in DNT cells from ER patients. Functional assays demonstrated that TIM3 blockade with sabatolimab restored T cell cytotoxicity, leading to enhanced leukemia cell apoptosis in ER patients. These findings highlight TIM3 as a critical regulator of T cell exhaustion and immune suppression in patients with ER and provide a rationale for the therapeutic use of TIM3 blockade in preventing and treating relapses after allo-HSCT.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"107"},"PeriodicalIF":13.5,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355862/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854981","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":"In-depth insight into tumor-infiltrating stromal cells linked to tertiary lymphoid structures and their prospective function in cancer immunotherapy.","authors":"Maedeh Radandish, Niloofar Mashhadi, Amir Hossein Aghayan, Motahareh Taghizadeh, Sara Salehianfard, Sheida Yahyazadeh, Omid Vakili, Somayeh Igder","doi":"10.1186/s40164-025-00695-8","DOIUrl":"10.1186/s40164-025-00695-8","url":null,"abstract":"<p><strong>Background and purpose: </strong>The tumor microenvironment (TME) is widely acknowledged as a pivotal regulator of cancer progression. However, the dualistic role of tertiary lymphoid structures (TLSs), which serve as critical immune hubs within the TME, remains incompletely characterized, particularly with respect to their context-dependent capacity to either inhibit or facilitate tumor development. This review aims to synthesize current understanding of the complex interactions between stromal cells and TLSs, addressing existing gaps in mechanistic insight and exploring therapeutic avenues to exploit TLS plasticity.</p><p><strong>Key reviewed topics: </strong>The current study critically reviews the mechanisms by which stromal components, including cancer-associated fibroblasts and endothelial cells, contribute to TLS neogenesis through chemokine-mediated recruitment of lymphocytes. Furthermore, it highlights the dual functional roles of TLSs as sites of both anti-tumor immune activation and immunosuppression, notably via the enrichment of regulatory T cells. The clinical implications of mature TLS presence, particularly their association with improved patient prognosis and enhanced therapeutic responsiveness, are also analyzed.</p><p><strong>Main conclusions: </strong>TLSs demonstrate a bifunctional nature, wherein their spatial organization and dynamic interactions with stromal elements dictate the balance between immune activation and tolerance within the TME. While mature TLSs are generally correlated with favorable clinical outcomes, their potential to foster immunosuppressive microenvironments necessitates the development of precision-targeted interventions. The interplay between stromal cells and TLSs represents a promising therapeutic axis for modulating the tumor immune milieu.</p><p><strong>Future perspectives: </strong>Future research should prioritize strategies aimed at promoting TLS maturation, disrupting immunosuppressive niches, and integrating TLS-modulating agents with existing immunotherapeutic regimens to enhance clinical efficacy. Additionally, the identification of robust biomarkers reflective of TLS functional states and the rigorous validation of stromal-targeted therapies within combinatorial treatment frameworks are imperative for advancing translational applications.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"105"},"PeriodicalIF":13.5,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12337498/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144816115","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":"An ureido-substituted benzenesulfonamide carbonic anhydrase inhibitor exerts a potent antitumor effect in vitro and in vivo.","authors":"Giorgia Gazzaroli, Camilla Tavani, Serena Filiberti, Maria Luisa Massardi, Marta Turati, Giulia Garattini, Thomas S Peat, Giuseppe Pieraccini, Andrea Angeli, Claudiu T Supuran, Fabrizio Carta, Arianna Giacomini, Roberto Ronca","doi":"10.1186/s40164-025-00690-z","DOIUrl":"10.1186/s40164-025-00690-z","url":null,"abstract":"<p><p>Carbonic anhydrase IX (CA IX) is a tumor-specific metallo-enzyme upregulated during hypoxic conditions and implicated in several pathophysiological processes where tissue pH regulation is required such as cancer, cell invasion, metastatic and stem-like features, drug resistance and recurrence. Indeed, CA IX expression has been correlated with poor prognosis, aggressiveness and disease progression in several solid tumors, and its targeting has been proposed as a therapeutic approach to treat aggressive cancers. To date, several CA IX targeting approaches have been developed to inhibit its activity in neoplastic tissues including the clinical grade (Phase Ib/II) ureido-substituted benzenesulfonamide SLC-0111, which has been widely investigated over the past years. In this study, we carried out a detailed characterization of a SLC-0111 derivative, FC-531, evaluating its anti-tumor potential in parallel with SLC-0111 on a panel of human cell lines representative of different cancer types. Finally, we evaluated the safety profile of FC-531 in vivo and demonstrated its capacity to reduce tumor growth and metastatization in vivo. Together, our data provide the rationale for the exploitation of FC-531 as a potent CA IX inhibitor for the management of different CA IX- expressing solid tumors.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"104"},"PeriodicalIF":13.5,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12333284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803948","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":"Incidence, mortality, and risk factors of bladder, kidney, prostate and testicular cancers in China and comparisons with the United States, the United Kingdom, Japan, and the Republic of Korea: an up-to-date overview based on the Global Burden of Disease 2021.","authors":"Gaohaer Kadeerhan, Zhongji Jiang, Hong Guo, Xinzhi Ma, Jin Zhang, Wenmin Guo, Jiedong Jia, Yibo Gao, Dongwen Wang","doi":"10.1186/s40164-025-00694-9","DOIUrl":"10.1186/s40164-025-00694-9","url":null,"abstract":"<p><strong>Background: </strong>The burden of genitourinary cancers has significantly changed in China over the recent decades. This study aims to identify the epidemiological trends and disparities in four common genitourinary cancers, including bladder, kidney, prostate, and testicular cancers, to inform public health strategies and interventions.</p><p><strong>Methods: </strong>Based on the Global Burden of Disease Study 2021, we examined incident cases, mortality, age-standardized incidence rates (ASIRs), age-standardized mortality rates (ASMRs), mortality-to-incidence ratios (MIRs), and risk factors for four genitourinary cancers globally and in the East Asia and Pacific, China, Japan, the Republic of Korea, the United States, and the United Kingdom from 1990 to 2021 across four specified age groups: 0-14, 15-49, 50-74, and ≥ 75 years. Trend analysis was conducted using Joinpoint analysis to calculate the average annual percentage changes (AAPCs). Decomposition analysis was performed to identify the population-level factors contributing to these trends.</p><p><strong>Results: </strong>In 2021, China reported approximately 266,887 incident cases and 108,589 deaths from genitourinary cancers, exhibiting distinct age-related patterns. ASIRs for male kidney cancer among those aged 0-14 years and testicular cancer among those aged ≥ 75 years, as well as ASMRs for male bladder cancer aged 15-49 years and testicular cancer aged ≥ 75 years, were higher in China than in the studied regions and countries. The MIRs for genitourinary cancers were generally higher in China. From 1990 to 2021, a notable increase in ASIRs for genitourinary cancers in both sexes, as well as ASMRs for male kidney and prostate cancers, across age groups ranging from 15 to 49 years to ≥ 75 years was observed in China, accompanied by higher AAPCs. The decomposition analysis identified the key population-level contributors to the incidence and mortality trends of genitourinary cancers, highlighting the varying influences of aging, population growth, and epidemiological changes. Smoking-related genitourinary cancer deaths remained high in Chinese males, and mortality related to high body mass index for kidney cancer and elevated fasting plasma glucose levels for bladder cancer also increased.</p><p><strong>Conclusions: </strong>The distinct age-specific patterns, elevated rates within specific age groups, and marked upward temporal trends of genitourinary cancers in China underscore the critical need for targeted, age-stratified public health interventions.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"103"},"PeriodicalIF":13.5,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12329898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793875","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":"Bisecting GlcNAc enhances CD8⁺ T cell-mediated killing of breast cancer by suppressing PD-L1 expression and its binding to PD-1.","authors":"Xueting Ren, Jinpeng Wu, Jing Li, Zhen Zhai, Xiang Li, Feng Guan, Meng Wang, Xiaobin Ma, Zengqi Tan, Huafeng Kang, Shuai Lin","doi":"10.1186/s40164-025-00693-w","DOIUrl":"10.1186/s40164-025-00693-w","url":null,"abstract":"<p><strong>Background: </strong>The abundance of PD-L1 on the surface of tumor cells is a critical factor in sensitizing these cells to T cell-mediated immune killing. While abnormal glycosylation of PD-L1 is known to influence its expression and function, the precise regulatory mechanisms remain unclear.</p><p><strong>Methods: </strong>This study utilized bioinformatics analysis to explore the role of MGAT3, a key gene involved in the formation of the bisecting GlcNAc structure, in breast cancer (BC). Experimental approaches were employed to increase bisecting GlcNAc levels in BC cells, followed by assessments of PD-L1 expression, CD8⁺ T cell-mediated cytotoxicity, extracellular vesicle (EV)-associated PD-L1, and PD-L1/PD-1 interaction. Additionally, forskolin, a bisecting GlcNAc agonist, was combined with anti-PD-L1 antibody to evaluate its antitumor effects in vivo.</p><p><strong>Results: </strong>MGAT3 was found to be expressed at low levels in BC tissues but positively correlated with CD8⁺ T cell infiltration. Elevating bisecting GlcNAc levels in BC cells significantly enhanced the cytotoxic efficacy of CD8⁺ T cells. High bisecting GlcNAc modification promoted PD-L1 degradation via the lysosomal pathway, reducing PD-L1 expression and its binding to PD-1. Furthermore, increased bisecting GlcNAc levels reduced PD-L1 in tumor cell-derived EVs, impairing the EVs' ability to block CD8⁺ T cells and indirectly enhancing T cell cytotoxicity. The combined use of forskolin and anti-PD-L1 antibody significantly increased CD8⁺ T cell abundance and activity, achieving a more effective antitumor response in vivo.</p><p><strong>Conclusions: </strong>These findings demonstrate that enhancing bisecting GlcNAc modification in BC cells promotes PD-L1 degradation and inhibits its binding to PD-1, thereby boosting CD8⁺ T cell-mediated cytotoxicity, providing a promising strategy for immune modulation in BC therapy.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"102"},"PeriodicalIF":13.5,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12323189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783895","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}