Jingwen Lv , Wei Zhu , Xin Xie , Chao Tian , Chengyang Zhu , Zongfeng Hu , Yixiao Li , Mingxia Shao , Wenqi Liu , Di Ma , Shengrun Wang , Xiaopeng Li , Jingfeng Li
{"title":"表达白细胞介素12的工程溶瘤性单纯疱疹病毒抑制肝癌的致瘤性","authors":"Jingwen Lv , Wei Zhu , Xin Xie , Chao Tian , Chengyang Zhu , Zongfeng Hu , Yixiao Li , Mingxia Shao , Wenqi Liu , Di Ma , Shengrun Wang , Xiaopeng Li , Jingfeng Li","doi":"10.1016/j.bbadis.2025.168033","DOIUrl":null,"url":null,"abstract":"<div><div>Oncolytic viruses (OVs) mediate anticancer effects through direct oncolytic activity and the expression of immunomodulatory transgenes. Talimogene laherparepvec (T-VEC), a genetically modified oncolytic herpes simplex virus type 1 (HSV-1) engineered to secrete granulocyte-macrophage colony stimulating factor (GM-CSF), has received United States Food and Drug Administration (FDA) approval for melanoma treatment. However, the clinical efficacy of early generation OVs like T-VEC remains limited, highlighting the need to enhance their antitumor potency and immune activation capacity. Interleukin-12 (IL-12) is a potent immunostimulatory cytokine that promotes Th1-type responses, triggering interferon-γ production by natural killer (NK) cells, CD4<sup>+</sup> T cells and CD8<sup>+</sup> T cells, thereby exhibiting robust antitumor activity. In this study, we constructed two recombinant HSV-1, oHSV-GMCSF and oHSV-IL12, and evaluated their antitumor effects, alone or in combination, in H22 murine hepatocellular carcinoma (HCC) model. Strikingly, oHSV-IL12 monotherapy achieved complete tumor eradication, surpassing the efficacy of oHSV-GMCSF. RNA sequencing analysis revealed that oHSV-IL12 treatment enhanced intratumoral lymphocyte infiltration and activation while upregulating immune-related genes and pathways. Notably, the oHSV-IL12 monotherapy showed comparable therapeutic outcomes to the combination of oHSV-GMCSF and oHSV-IL12 in both rechallenge and survival experiments. These findings position oHSV-IL12 as a promising novel candidate for HCC immunotherapy.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 1","pages":"Article 168033"},"PeriodicalIF":4.2000,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Engineered oncolytic herpes simplex virus expressing interleukin 12 suppresses tumorigenicity of hepatocellular carcinoma\",\"authors\":\"Jingwen Lv , Wei Zhu , Xin Xie , Chao Tian , Chengyang Zhu , Zongfeng Hu , Yixiao Li , Mingxia Shao , Wenqi Liu , Di Ma , Shengrun Wang , Xiaopeng Li , Jingfeng Li\",\"doi\":\"10.1016/j.bbadis.2025.168033\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Oncolytic viruses (OVs) mediate anticancer effects through direct oncolytic activity and the expression of immunomodulatory transgenes. Talimogene laherparepvec (T-VEC), a genetically modified oncolytic herpes simplex virus type 1 (HSV-1) engineered to secrete granulocyte-macrophage colony stimulating factor (GM-CSF), has received United States Food and Drug Administration (FDA) approval for melanoma treatment. However, the clinical efficacy of early generation OVs like T-VEC remains limited, highlighting the need to enhance their antitumor potency and immune activation capacity. Interleukin-12 (IL-12) is a potent immunostimulatory cytokine that promotes Th1-type responses, triggering interferon-γ production by natural killer (NK) cells, CD4<sup>+</sup> T cells and CD8<sup>+</sup> T cells, thereby exhibiting robust antitumor activity. In this study, we constructed two recombinant HSV-1, oHSV-GMCSF and oHSV-IL12, and evaluated their antitumor effects, alone or in combination, in H22 murine hepatocellular carcinoma (HCC) model. Strikingly, oHSV-IL12 monotherapy achieved complete tumor eradication, surpassing the efficacy of oHSV-GMCSF. RNA sequencing analysis revealed that oHSV-IL12 treatment enhanced intratumoral lymphocyte infiltration and activation while upregulating immune-related genes and pathways. Notably, the oHSV-IL12 monotherapy showed comparable therapeutic outcomes to the combination of oHSV-GMCSF and oHSV-IL12 in both rechallenge and survival experiments. These findings position oHSV-IL12 as a promising novel candidate for HCC immunotherapy.</div></div>\",\"PeriodicalId\":8821,\"journal\":{\"name\":\"Biochimica et biophysica acta. 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Molecular basis of disease","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0925443925003813","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Oncolytic viruses (OVs) mediate anticancer effects through direct oncolytic activity and the expression of immunomodulatory transgenes. Talimogene laherparepvec (T-VEC), a genetically modified oncolytic herpes simplex virus type 1 (HSV-1) engineered to secrete granulocyte-macrophage colony stimulating factor (GM-CSF), has received United States Food and Drug Administration (FDA) approval for melanoma treatment. However, the clinical efficacy of early generation OVs like T-VEC remains limited, highlighting the need to enhance their antitumor potency and immune activation capacity. Interleukin-12 (IL-12) is a potent immunostimulatory cytokine that promotes Th1-type responses, triggering interferon-γ production by natural killer (NK) cells, CD4+ T cells and CD8+ T cells, thereby exhibiting robust antitumor activity. In this study, we constructed two recombinant HSV-1, oHSV-GMCSF and oHSV-IL12, and evaluated their antitumor effects, alone or in combination, in H22 murine hepatocellular carcinoma (HCC) model. Strikingly, oHSV-IL12 monotherapy achieved complete tumor eradication, surpassing the efficacy of oHSV-GMCSF. RNA sequencing analysis revealed that oHSV-IL12 treatment enhanced intratumoral lymphocyte infiltration and activation while upregulating immune-related genes and pathways. Notably, the oHSV-IL12 monotherapy showed comparable therapeutic outcomes to the combination of oHSV-GMCSF and oHSV-IL12 in both rechallenge and survival experiments. These findings position oHSV-IL12 as a promising novel candidate for HCC immunotherapy.
期刊介绍:
BBA Molecular Basis of Disease addresses the biochemistry and molecular genetics of disease processes and models of human disease. This journal covers aspects of aging, cancer, metabolic-, neurological-, and immunological-based disease. Manuscripts focused on using animal models to elucidate biochemical and mechanistic insight in each of these conditions, are particularly encouraged. Manuscripts should emphasize the underlying mechanisms of disease pathways and provide novel contributions to the understanding and/or treatment of these disorders. Highly descriptive and method development submissions may be declined without full review. The submission of uninvited reviews to BBA - Molecular Basis of Disease is strongly discouraged, and any such uninvited review should be accompanied by a coverletter outlining the compelling reasons why the review should be considered.