Targeted inhibition of STAT3 induces immunogenic cell death of hepatocellular carcinoma cells via glycolysis
In hepatocellular carcinoma (HCC), the signal transducer and activator of transcription 3 (STAT3) is present in an overactive state that is closely related to tumour development and immune escape. STAT3 inhibition reshapes the tumour immune microenvironment, but the underlying mechanisms have not be...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-08-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.13263 |
| _version_ | 1828188995270475776 |
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| author | Ya Li Zhenwei Song Qiuju Han Huajun Zhao Zhaoyi Pan Zhengyang Lei Jian Zhang |
| author_facet | Ya Li Zhenwei Song Qiuju Han Huajun Zhao Zhaoyi Pan Zhengyang Lei Jian Zhang |
| author_sort | Ya Li |
| collection | DOAJ |
| description | In hepatocellular carcinoma (HCC), the signal transducer and activator of transcription 3 (STAT3) is present in an overactive state that is closely related to tumour development and immune escape. STAT3 inhibition reshapes the tumour immune microenvironment, but the underlying mechanisms have not been fully clarified. We found that STAT3 inhibition could induce immunogenic cell death (ICD) of HCC cells via translocation of the “eat me” molecule calreticulin to the cell surface and a significant reduction in the expression of the “don’t eat me” molecule leucocyte surface antigen CD47. STAT3 inhibition promoted dendritic cell (DC) activation and enhanced the recognition and phagocytosis of HCC cells by macrophages. Furthermore, STAT3 inhibition prevented the expression of key glycolytic enzymes, facilitating the induction of ICD in HCC. Interestingly, STAT3 directly regulated the transcription of CD47 and solute carrier family 2 member 1 (SLC2A1; also known as GLUT1). In subcutaneous and orthotopic transplantation mouse tumour models, the STAT3 inhibitor napabucasin prevented tumour growth and induced the expression of calreticulin and the protein disulfide isomerase family A member 3 (PDIA3; also known as ERp57) but suppressed that of CD47 and GLUT1. Meanwhile, the amount of tumour‐infiltrated DCs and macrophages increased, along with the expression of costimulatory molecules. More CD4+ and CD8+ T cells accumulated in tumour tissues, and CD8+ T cells had lower expression of checkpoint molecules such as lymphocyte activation gene 3 protein (LAG‐3) and programmed cell death protein 1 (PD‐1). Significantly, the antitumour immune memory response was induced by treatment targeting STAT3. These findings provide a new mechanism for targeting STAT3‐induced ICD in HCC, and confirms STAT3 as a potential target for the treatment of HCC via reshaping the tumour immune microenvironment. |
| first_indexed | 2024-04-12T07:58:35Z |
| format | Article |
| id | doaj.art-4ed4ca9569b943e7be577d5bd5a22f10 |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-04-12T07:58:35Z |
| publishDate | 2022-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-4ed4ca9569b943e7be577d5bd5a22f102022-12-22T03:41:24ZengWileyMolecular Oncology1574-78911878-02612022-08-0116152861288010.1002/1878-0261.13263Targeted inhibition of STAT3 induces immunogenic cell death of hepatocellular carcinoma cells via glycolysisYa Li0Zhenwei Song1Qiuju Han2Huajun Zhao3Zhaoyi Pan4Zhengyang Lei5Jian Zhang6Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences Shandong University Jinan ChinaInstitute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences Shandong University Jinan ChinaInstitute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences Shandong University Jinan ChinaInstitute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences Shandong University Jinan ChinaInstitute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences Shandong University Jinan ChinaInstitute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences Shandong University Jinan ChinaInstitute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences Shandong University Jinan ChinaIn hepatocellular carcinoma (HCC), the signal transducer and activator of transcription 3 (STAT3) is present in an overactive state that is closely related to tumour development and immune escape. STAT3 inhibition reshapes the tumour immune microenvironment, but the underlying mechanisms have not been fully clarified. We found that STAT3 inhibition could induce immunogenic cell death (ICD) of HCC cells via translocation of the “eat me” molecule calreticulin to the cell surface and a significant reduction in the expression of the “don’t eat me” molecule leucocyte surface antigen CD47. STAT3 inhibition promoted dendritic cell (DC) activation and enhanced the recognition and phagocytosis of HCC cells by macrophages. Furthermore, STAT3 inhibition prevented the expression of key glycolytic enzymes, facilitating the induction of ICD in HCC. Interestingly, STAT3 directly regulated the transcription of CD47 and solute carrier family 2 member 1 (SLC2A1; also known as GLUT1). In subcutaneous and orthotopic transplantation mouse tumour models, the STAT3 inhibitor napabucasin prevented tumour growth and induced the expression of calreticulin and the protein disulfide isomerase family A member 3 (PDIA3; also known as ERp57) but suppressed that of CD47 and GLUT1. Meanwhile, the amount of tumour‐infiltrated DCs and macrophages increased, along with the expression of costimulatory molecules. More CD4+ and CD8+ T cells accumulated in tumour tissues, and CD8+ T cells had lower expression of checkpoint molecules such as lymphocyte activation gene 3 protein (LAG‐3) and programmed cell death protein 1 (PD‐1). Significantly, the antitumour immune memory response was induced by treatment targeting STAT3. These findings provide a new mechanism for targeting STAT3‐induced ICD in HCC, and confirms STAT3 as a potential target for the treatment of HCC via reshaping the tumour immune microenvironment.https://doi.org/10.1002/1878-0261.13263glycolysisHCCICDimmune environmentSTAT3 |
| spellingShingle | Ya Li Zhenwei Song Qiuju Han Huajun Zhao Zhaoyi Pan Zhengyang Lei Jian Zhang Targeted inhibition of STAT3 induces immunogenic cell death of hepatocellular carcinoma cells via glycolysis Molecular Oncology glycolysis HCC ICD immune environment STAT3 |
| title | Targeted inhibition of STAT3 induces immunogenic cell death of hepatocellular carcinoma cells via glycolysis |
| title_full | Targeted inhibition of STAT3 induces immunogenic cell death of hepatocellular carcinoma cells via glycolysis |
| title_fullStr | Targeted inhibition of STAT3 induces immunogenic cell death of hepatocellular carcinoma cells via glycolysis |
| title_full_unstemmed | Targeted inhibition of STAT3 induces immunogenic cell death of hepatocellular carcinoma cells via glycolysis |
| title_short | Targeted inhibition of STAT3 induces immunogenic cell death of hepatocellular carcinoma cells via glycolysis |
| title_sort | targeted inhibition of stat3 induces immunogenic cell death of hepatocellular carcinoma cells via glycolysis |
| topic | glycolysis HCC ICD immune environment STAT3 |
| url | https://doi.org/10.1002/1878-0261.13263 |
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