{"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":null,"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<sup>+</sup> 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":13.5000,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355751/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental Hematology & Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s40164-025-00696-7","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: 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).
Methods: 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.
Results: 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.
Conclusion: 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.
期刊介绍:
Experimental Hematology & Oncology is an open access journal that encompasses all aspects of hematology and oncology with an emphasis on preclinical, basic, patient-oriented and translational research. The journal acts as an international platform for sharing laboratory findings in these areas and makes a deliberate effort to publish clinical trials with 'negative' results and basic science studies with provocative findings.
Experimental Hematology & Oncology publishes original work, hypothesis, commentaries and timely reviews. With open access and rapid turnaround time from submission to publication, the journal strives to be a hub for disseminating new knowledge and discussing controversial topics for both basic scientists and busy clinicians in the closely related fields of hematology and oncology.