2. Academic Validation
  3. Dual-Responsive Epigenetic Inhibitor Nanoprodrug Combined with Oncolytic Virus Synergistically Boost Cancer Immunotherapy by Igniting Gasdermin E-Mediated Pyroptosis

Dual-Responsive Epigenetic Inhibitor Nanoprodrug Combined with Oncolytic Virus Synergistically Boost Cancer Immunotherapy by Igniting Gasdermin E-Mediated Pyroptosis

  • ACS Nano. 2024 Jul 22. doi: 10.1021/acsnano.4c03034.
Yuan-Yuan Wang 1,  Jingting Wang 2,  Shuo Wang 1,  Qi-Chao Yang 1,  An Song 1,  Meng-Jie Zhang 1,  Wen-Da Wang 1,  Yuan-Tong Liu 1,  Junjie Zhang 1,  Wei-Ming Wang 3,  Zhigang Xu 2 4,  Zhi-Jun Sun 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430079, People's Republic of China.
  • 2 Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of Education, School of Materials and Energy & Chongqing Engineering Research Center for Micro-Nano Biomedical Materials and Devices, Southwest University, Chongqing 400715, People's Republic of China.
  • 3 Department of Oral and Maxillofacial Surgery, Center of Stomatology, Institute of Oral Precancerous Lesions, Xiangya Hospital, Research Center of Oral and Maxillofacial Tumor, National Clinical Research Center for Geriatric Disorders, Central South University, Changsha 410008, People's Republic of China.
  • 4 Yibin Academy of Southwest University, Yibin 644000, People's Republic of China.
PMID: 39038109 DOI: 10.1021/acsnano.4c03034
Abstract

Cancer Immunotherapy has emerged as a promising approach for the treatment of various cancers. However, the immunosuppressive tumor microenvironment (TME) limits the efficacy of current immunotherapies. In this study, we designed a dual-responsive DNA Methyltransferase Inhibitor nanoprodrug ACNPs for combination therapy with oncolytic herpes simplex virus (oHSV). We found that the epigenetic inhibitor 5-Azacytidine (5-Aza) upregulated gasdermin E (GSDME) expression at the gene level, whereas the oHSV decreased the ubiquitination and degradation of GSDME to elevate its levels. Based on these observations, we further discovered that ACNPs and oHSV synergistically enhanced GSDME-mediated Pyroptosis. Additionally, the combination therapy of ACNPs and oHSV effectively inhibited tumor growth, remodeled the immunosuppressive TME, and improved the efficacy of Immune Checkpoint blockade (ICB) therapy. These results demonstrate the potential to overcome immunosuppression through synergistic combinations, offering a promising approach for Cancer Immunotherapy.

Keywords

GSDME; cancer immunotherapy; epigenetic; oncolytic virus; pyroptosis.

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