4.8 Article

An Inter-Supplementary Biohybrid System Based on Natural Killer Cells for the Combinational Immunotherapy and Virotherapy of Cancer

期刊

ADVANCED SCIENCE
卷 9, 期 2, 页码 -

出版社

WILEY
DOI: 10.1002/advs.202103470

关键词

anticancer immunity; cell carriers; natural killer cells; oncolytic adenovirus; tumor-targeted delivery

资金

  1. National Natural Science Foundation of China [81802765, 31900993]
  2. National Key R&D Program of China [2016YFD0500202]
  3. Natural Science Foundation of Jiangsu Province for Young Scientists [BK20160478]
  4. China Postdoctoral Science Foundation [2019M661956, 2020T130561]
  5. Postdoctoral Science Foundation Funded Project of Jiangsu Province [2019K066]
  6. Yangzhou University [5020/137011461]
  7. Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)

向作者/读者索取更多资源

An NK cell-mediated Ad delivery system has been developed for combinational immunotherapy and virotherapy of cancer, which not only enhances antitumor immunity but also relieves immunosuppression in the tumor microenvironment. In vitro and in vivo data demonstrate the excellent antitumor and antimetastatic functions of the Ad@NK system by destroying tumor cells, inducing immunogenic cell death, and immunomodulating TME.
Oncolytic adenoviruses (Ads) have gained great attention in cancer therapy because they cause direct cytolytic infection and indirectly induce antitumor immunity. However, their efficacy is compromised by host antiviral immune response, poor tumor delivery, and the immunosuppressive tumor microenvironment (TME). Here, a natural killer (NK) cell-mediated Ad delivery system (Ad@NK) is generated by harnessing the merits of the two components for combinational immunotherapy and virotherapy of cancer. In this biohybrid system, NK cells with a tumor-homing tropism act as bioreactors and shelters for the loading, protection, replication, amplification, and release of Ads, thereby leading to a highly efficient systemic tumor-targeted delivery. As feedback, Ad infection offers NK cells an enhanced antitumor immunity by activating type I interferon signaling in a STAT4-granzyme B-dependent manner. Moreover, it is found that the Ad@NK system can relieve immunosuppression in the TME by promoting the maturation of dendritic cells and the polarization of macrophages to M1 phenotype. Both in vitro and in vivo data indicate the excellent antitumor and antimetastatic functions of Ad@NKs by destroying tumor cells, inducing immunogenic cell death, and immunomodulating TME. This work provides a clinical basis for improved oncolytic virotherapy in combination with NK cell therapy based on the inter-supplementary biohybrid system.

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