Experimental Hematology & Oncology最新文献

{"title":"Tumor-priming CD8⁺ natural killer T-like cells as an efficient novel cell therapy for relapsed/refractory multiple myeloma.","authors":"Juheon Lee, Eunjeong Choi, Bohwa Han, Jeong-A Kim, Dana Jung, Kyeong-Hee Kim, Sung Yong Oh, Sung-Hyun Kim, Kyung-Soo Ha, Ji-Hoon Kim, Ji Hyun Lee, Duck Cho, Junsang Doh, Seok-Ho Kim","doi":"10.1186/s40164-025-00707-7","DOIUrl":"10.1186/s40164-025-00707-7","url":null,"abstract":"<p><strong>Background: </strong>Relapsed and refractory multiple myeloma (RRMM) remains a major clinical challenge, as most patients eventually relapse following standard treatments and are left with limited therapeutic options. Although b-cell maturation antigen (BCMA) CAR-T cell therapy has recently shown remarkable efficacy in select patients, broader implementation is hindered by its reliance on autologous cells, prolonged manufacturing timelines, high costs, and severe immune-related toxicities. These challenges have prompted an urgent demand for safer, more accessible, and rapidly applicable immunotherapeutic alternatives.</p><p><strong>Methods: </strong>CBMC (cord blood mononuclear cells) were cultured with irradiated BMMC (bone marrow mononuclear cells) from RRMM patients in the presence of defined cytokines, aiming to develop a new therapeutic immune cell product for RRMM. Their phenotypic and functional characteristics, including non-MHC-restricted and MHC-restricted cytotoxicity mechanisms, were analyzed using surface marker profiling, cytokine secretion assays, in vitro cytotoxicity assays, functional and blocking assays. Antitumor activity was evaluated in xenograft mouse models using MM.1 S and RPMI-8226 cells.</p><p><strong>Results: </strong>We successfully generated CD8⁺ NKT-like cells through tumor priming, which exhibited potent cytotoxicity and elevated cytokine production against multiple myeloma cell lines and primary RRMM samples. Mechanistically, tumor-priming CD8⁺ NKT-like cells (TPNC) cytotoxicity was mediated by both non-MHC-restricted pathways involving LFA-1 and DNAM-1, and MHC-restricted, TCR-mediated recognition. TPNC efficiently formed immune synapses, rapidly polarized cytotoxic granules, and engaged in serial killing. In xenograft models, TPNC significantly suppressed tumor progression, prolonged survival, and persisted in circulation without observable toxicity. Based on these findings, we extended the tumor-priming strategy to acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), successfully generating TPNC with robust cytotoxic activity. In ALL samples, TPNC exhibited cytotoxicity comparable to anti-CD19 CAR-NK cells.</p><p><strong>Conclusions: </strong>TPNC represents a novel cytotoxic lymphocyte product generated through tumor-driven priming. Their dual recognition capacity, functional versatility, and favorable safety profile highlight their potential as a scalable and personalized immunotherapy platform for hematologic malignancies.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"116"},"PeriodicalIF":13.5,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12482268/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191532","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":"FGL1-mediated lymph node metastasis in stage T1 non-small cell lung cancer: therapeutic targeting.","authors":"Xi-Yang Tang, Run-Ze Zhang, Zhi-Bo Feng, Yu-Long Zhou, Wei-Guang Du, Chen Shu, Yang Shen, Meng-Chao Li, Jun-Chao Cai, Xiao-Long Yan, Nan Ma, Jin-Bo Zhao","doi":"10.1186/s40164-025-00709-5","DOIUrl":"10.1186/s40164-025-00709-5","url":null,"abstract":"<p><strong>Background: </strong>Approximately 30% of patients with stage T1 non-small cell lung cancer (NSCLC) have mediastinal (N2) lymph node metastasis; however, the underlying mechanism remains unclear.</p><p><strong>Methods: </strong>The cells likely mediating N2 lymph node metastasis in T1 NSCLC were identified by single-cell sequencing. The expression and function of the main functional gene high fibrinogen-like protein 1 (FGL1) in this cell subgroup were analyzed by single-cell analysis. Transcriptome sequencing, metabolome sequencing, and mass spectrometry combined with in vitro and in vivo experiments were conducted, and therapeutic validation was performed using shFGL1_AAV9 and shFGL1_AAV6.</p><p><strong>Results: </strong>A novel cell subgroup characterized by FGL1 expression was identified (CCNE1(+) cells). FGL1 expression coincided with the appearance of this cell subgroup, suggesting that FGL1 + cells mediate T1 NSCLC N2 lymph node metastasis. Mass spectrometry combined with transcription sequencing and metabonomics revealed that FGL1 may affect glycolysis regulators and participate in epithelial-to-mesenchymal transition in NSCLC via the PI3K/AKT/HIF-1α pathway. Further analyses suggested that FGL1 promotes tumor proliferation, metastasis, and lymph tube formation, ultimately inducing lymph node metastasis. This was verified in vivo and in vitro. FGL1 knockdown inhibited these processes. Finally, shFGL1_AAV9 and shFGL1_AAV6 were verified as novel targeted therapies to knock down FGL1 in vivo, supporting the identification of new therapeutic targets to inhibit NSCLC metastasis.</p><p><strong>Conclusion: </strong>We elucidated the role of FGL1 in NSCLC, proposing that FGL1 acts like a \"shield machine cutter\" in mediating T1 NSCLC N2 lymph node tube formation, creating metastasis channels. This provides the basis for novel FGL1-targeting treatment strategies.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"117"},"PeriodicalIF":13.5,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481761/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191558","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":"Transforming cancer immunotherapy: integration of distinct immune-based approaches as redefined dual immunotherapy with potential third-sensitizer.","authors":"Yuqian Wang, Cheng Jiang, Huiling Zhou, Rui Han","doi":"10.1186/s40164-025-00705-9","DOIUrl":"10.1186/s40164-025-00705-9","url":null,"abstract":"<p><p>This review introduces a paradigm-shifting concept of Dual Distinct Immunotherapy (DDI), which strategically integrates two distinct immunotherapeutic modalities to overcome the limitations of current monotherapies and dual immune checkpoint inhibitor (ICI) combinations. The concept of DDI extends beyond traditional ICI combinations to encompass various innovative pairings: ICIs with oncolytic viruses (OVs), adoptive cell therapies (CAR-T/TIL), cancer vaccines, or cytokine therapies. These combinations demonstrate unique synergistic mechanisms and enhanced therapeutic potential through multi-faceted immune activation. Significantly, this work advances the field by analyzing potential third-agent sensitizers to complement DDI strategies. We systematically evaluate emerging candidates including PCNA inhibitors, HDAC inhibitors, and carbonic anhydrase inhibitors, focusing on their ability to modulate the tumor microenvironment and enhance immunotherapy responses. This \"DDI + 1\" approach targets alternative pathways to overcome resistance mechanisms and expand treatment efficacy to traditionally immunotherapy-resistant cancers. Through comprehensive analysis of preclinical evidence and ongoing clinical trials, we address critical challenges in immunotherapy, including primary and acquired resistance, cold tumor conversion, and pathway exhaustion. The review synthesizes current findings while proposing innovative solutions and future research directions. Our framework demonstrates how strategic integration of multiple immune-based approaches can significantly improve therapeutic outcomes across diverse cancer types, potentially revolutionizing cancer treatment paradigms. This concept of DDI, enhanced by rational third-agent selection, represents a promising direction for addressing urgent clinical needs in oncology. By establishing a theoretical foundation for this approach, we aim to guide future research and clinical applications in cancer immunotherapy.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"114"},"PeriodicalIF":13.5,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12482737/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191524","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":"Overall survival of recurrent/metastatic head & neck squamous cell carcinoma patients progressing after ≥ 1 line of systemic therapy, treated with MVX-ONCO-1, a novel, first in class cell encapsulation-based immunotherapy: results of SAKK 11/16, a phase IIa trial.","authors":"Eugenio Fernandez, Rémi Vernet, Muriel Urwyler, Olivier Von Rohr, Emily Charrier, Marie-Claude Belkouch, Valentin Saingier, Fabien Courtout, Claudio DeVito, Virginie Ancrenaz, Nicolas Dulguerov, Wolfram Karenovics, Julien Grogg, Jessica Renaux, Katrin Gobat, Gisela Müller, Tomas Brezina, Tamara Rordorf, Markus Joerger, Olivier Michielin, Jean Villard, Nicolas Mach","doi":"10.1186/s40164-025-00703-x","DOIUrl":"10.1186/s40164-025-00703-x","url":null,"abstract":"<p><strong>Background: </strong>Over the past two decades, most cancer vaccines have failed to be developed clinically. The lack of efficient priming with specific tumor antigens and/or weak adjuvants may explain this poor success rate. MVX-ONCO-1, a personalized cell-based vaccine, combines inactivated autologous tumor cells and encapsulated allogeneic human cells genetically engineered to produce granulocyte-macrophage colony stimulating factor (GM-CSF). This unique technology allows sustained local delivery of strong adjuvant at the vaccination site. The combination of inactivated autologous tumor cells and potent local adjuvant delivery addresses these two unmet critical steps and may recapitulate in patients the successful combination observed in experimental models.</p><p><strong>Methods: </strong>The SAKK 11/16, a Phase IIa trial with Overall Survival (OS) as the primary endpoint was the first efficacy study evaluating MVX-ONCO-1. Patients with Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC) progressing after at least one line of systemic therapy were enrolled with 50% of patients alive at 26 weeks as the primary objective.</p><p><strong>Results: </strong>In this hard-to-treat population, SAKK 11/16 met the primary endpoint, with 68.8% of patients alive at 6 months. The median OS was 11.4 months, with 32% of the patients alive after 18 months. Complete and partial responses were observed on MVX-ONCO-1 monotherapy. Moreover, all patients who developed a positive DTH reaction to their tumor cells upon vaccination survived at 12 months. Additionally, patients living for more than 12 months had higher circulating antibody titers against tumor-associated antigens. Explorative analysis looking at median OS from the start of anti-PD-1 therapy was 21.7 months. In addition, no new safety signals with no systemic adverse events (AE) related to the treatment and no manufacturing issues were observed in this multicenter trial.</p><p><strong>Conclusions: </strong>These findings suggest that MVX-ONCO-1 can induce a coordinated immune response with clinical benefits as a standalone treatment, leading to prolonged survival. This effect may be enhanced by previous exposure to immune checkpoint inhibitors. Trial registration (ClinicalTrials.gov): NCT02999646.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"113"},"PeriodicalIF":13.5,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12398963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144947907","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":"IL-7-PD-L1 nano-antibody mediated \"zipper\" effect augments the tumoricidal activity of tumor-infiltrating lymphocytes.","authors":"Zhongjie Yu, Zhen Guo, Bin Jiang, Yueshu Zhu, Lin Shao, Xinhua Zhang, Yi Zhao, Di Wu, Aotian Xu","doi":"10.1186/s40164-025-00702-y","DOIUrl":"10.1186/s40164-025-00702-y","url":null,"abstract":"<p><p>Cancer represents a pressing global health concern, characterized by a substantial number of unmet clinical needs. Cell therapy has emerged as a promising and efficacious approach for cancer treatment, particularly tumor-infiltrating lymphocytes (TILs), which have demonstrated remarkable improvements in patients' overall survival rates across various clinical studies. However, the tumor microenvironment exerts a adverse effect on TILs, leading to their rapid exhaustion and functional disorder. Consequently, this impedes their ability to effectively eradicate tumors and thus hinders the achievement of the anticipated therapeutic efficacy. Here, we employed lentiviral vector-mediated genetic engineering to manipulate TILs for the expression of TIGIT shRNA, IL-7-PD-L1 nano-antibody fusion protein, and the 'molecular switch' HuEGFRt. The engineered TILs exhibited higher viability, reinforced cell expansion, and reduced reliance on IL-2. The stem-like proportion of engineered TILs is significantly augmented, and their activation level is enhanced when co-cultured with tumor cells. Meanwhile, the engineered TILs exert sustained cytotoxicity after repeated stimulation from tumor cells. The use of Cetuximab has been demonstrated in vitro to induce specific apoptosis of engineered TILs through HuEGFRt, thereby ensuring safety throughout the treatment process. In the mouse tumor model, following infusion of engineered TILs, the tumor volume significantly reduced, once again demonstrating the effectiveness of engineered TILs. The findings of our study demonstrate the exceptional performance of engineered TILs, which undoubtedly holds great promise for the clinical application of engineered TILs, ultimately benefiting a larger population of cancer patients.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"112"},"PeriodicalIF":13.5,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12398053/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144947952","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 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}