The anticancer thiosemicarbazone triapine exerts immune-enhancing activities via immunogenic cell death induction and FAS upregulation
Abstract The anticancer thiosemicarbazone Triapine is currently in a phase III clinical trial in combination with radiation therapy and cisplatin. Noteworthy, while radiotherapy induces an immune-activating cell death, so called immunogenic cell death (ICD), cisplatin possesses immunomodulatory and...
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BMC
2025-08-01
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| Series: | Experimental Hematology & Oncology |
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| Online Access: | https://doi.org/10.1186/s40164-025-00700-0 |
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| author | Bianca Stiller Alessia Stefanelli Hemma Schueffl Marlene Mathuber Nadiya Skorokhyd Judith Gufler Christine Pirker Martin Holcmann Rostyslav Panchuk Maria Sibilia Doris Marko Walter Berger Christian R. Kowol Sonja Hager Petra Heffeter |
| author_facet | Bianca Stiller Alessia Stefanelli Hemma Schueffl Marlene Mathuber Nadiya Skorokhyd Judith Gufler Christine Pirker Martin Holcmann Rostyslav Panchuk Maria Sibilia Doris Marko Walter Berger Christian R. Kowol Sonja Hager Petra Heffeter |
| author_sort | Bianca Stiller |
| collection | DOAJ |
| description | Abstract The anticancer thiosemicarbazone Triapine is currently in a phase III clinical trial in combination with radiation therapy and cisplatin. Noteworthy, while radiotherapy induces an immune-activating cell death, so called immunogenic cell death (ICD), cisplatin possesses immunomodulatory and ICD-enhancing functions. Interestingly, although there are several indications that suggest that Triapine could also enhance the immune recognition of cancer cells, no investigations in this direction have been reported so far. Indeed, immune cells (especially cytotoxic T-cells) were found to enhance the anticancer activity of Triapine. This effect might be based on endoplasmic reticulum (ER) stress induction, which on the one hand led to ICD of the cancer cells as indicated by ATP release, calreticulin exposure, high-mobility group box 1 secretion and in vivo vaccination experiments. On the other hand, the Triapine-induced ER stress resulted in FAS upregulation in cell culture as well as in vivo via NFκB signaling. This, in turn, rendered cancer cells more susceptible to FASL (predominantly expressed by lymphoid immune cells)-induced caspase 8-mediated apoptosis. Consequently, our study is the first to unveil the significant role of the (adaptive) immune system in the anticancer activity of Triapine, positioning it as a promising partner for combination with immunotherapy and other immunogenic agents. |
| format | Article |
| id | doaj-art-1c770af2f5d24110aff5387af9df6571 |
| institution | Kabale University |
| issn | 2162-3619 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Experimental Hematology & Oncology |
| spelling | doaj-art-1c770af2f5d24110aff5387af9df65712025-08-24T11:12:08ZengBMCExperimental Hematology & Oncology2162-36192025-08-011411510.1186/s40164-025-00700-0The anticancer thiosemicarbazone triapine exerts immune-enhancing activities via immunogenic cell death induction and FAS upregulationBianca Stiller0Alessia Stefanelli1Hemma Schueffl2Marlene Mathuber3Nadiya Skorokhyd4Judith Gufler5Christine Pirker6Martin Holcmann7Rostyslav Panchuk8Maria Sibilia9Doris Marko10Walter Berger11Christian R. Kowol12Sonja Hager13Petra Heffeter14Center for Cancer Research and Comprehensive Cancer Center, Medical University of ViennaCenter for Cancer Research and Comprehensive Cancer Center, Medical University of ViennaCenter for Cancer Research and Comprehensive Cancer Center, Medical University of ViennaInstitute of Inorganic Chemistry, Faculty of Chemistry, University of ViennaDepartment of Regulation of Cell Proliferation and Apoptosis, Institute of Cell Biology, National Academy of Science of UkraineDepartment of Food Chemistry and Toxicology, Faculty of Chemistry, University of ViennaCenter for Cancer Research and Comprehensive Cancer Center, Medical University of ViennaCenter for Cancer Research and Comprehensive Cancer Center, Medical University of ViennaCenter for Cancer Research and Comprehensive Cancer Center, Medical University of ViennaCenter for Cancer Research and Comprehensive Cancer Center, Medical University of ViennaDepartment of Food Chemistry and Toxicology, Faculty of Chemistry, University of ViennaCenter for Cancer Research and Comprehensive Cancer Center, Medical University of ViennaInstitute of Inorganic Chemistry, Faculty of Chemistry, University of ViennaCenter for Cancer Research and Comprehensive Cancer Center, Medical University of ViennaCenter for Cancer Research and Comprehensive Cancer Center, Medical University of ViennaAbstract The anticancer thiosemicarbazone Triapine is currently in a phase III clinical trial in combination with radiation therapy and cisplatin. Noteworthy, while radiotherapy induces an immune-activating cell death, so called immunogenic cell death (ICD), cisplatin possesses immunomodulatory and ICD-enhancing functions. Interestingly, although there are several indications that suggest that Triapine could also enhance the immune recognition of cancer cells, no investigations in this direction have been reported so far. Indeed, immune cells (especially cytotoxic T-cells) were found to enhance the anticancer activity of Triapine. This effect might be based on endoplasmic reticulum (ER) stress induction, which on the one hand led to ICD of the cancer cells as indicated by ATP release, calreticulin exposure, high-mobility group box 1 secretion and in vivo vaccination experiments. On the other hand, the Triapine-induced ER stress resulted in FAS upregulation in cell culture as well as in vivo via NFκB signaling. This, in turn, rendered cancer cells more susceptible to FASL (predominantly expressed by lymphoid immune cells)-induced caspase 8-mediated apoptosis. Consequently, our study is the first to unveil the significant role of the (adaptive) immune system in the anticancer activity of Triapine, positioning it as a promising partner for combination with immunotherapy and other immunogenic agents.https://doi.org/10.1186/s40164-025-00700-0Anticancer therapyThiosemicarbazonesTriapineImmunogenic cell deathImmunomodulationAdaptive immune system |
| spellingShingle | Bianca Stiller Alessia Stefanelli Hemma Schueffl Marlene Mathuber Nadiya Skorokhyd Judith Gufler Christine Pirker Martin Holcmann Rostyslav Panchuk Maria Sibilia Doris Marko Walter Berger Christian R. Kowol Sonja Hager Petra Heffeter The anticancer thiosemicarbazone triapine exerts immune-enhancing activities via immunogenic cell death induction and FAS upregulation Experimental Hematology & Oncology Anticancer therapy Thiosemicarbazones Triapine Immunogenic cell death Immunomodulation Adaptive immune system |
| title | The anticancer thiosemicarbazone triapine exerts immune-enhancing activities via immunogenic cell death induction and FAS upregulation |
| title_full | The anticancer thiosemicarbazone triapine exerts immune-enhancing activities via immunogenic cell death induction and FAS upregulation |
| title_fullStr | The anticancer thiosemicarbazone triapine exerts immune-enhancing activities via immunogenic cell death induction and FAS upregulation |
| title_full_unstemmed | The anticancer thiosemicarbazone triapine exerts immune-enhancing activities via immunogenic cell death induction and FAS upregulation |
| title_short | The anticancer thiosemicarbazone triapine exerts immune-enhancing activities via immunogenic cell death induction and FAS upregulation |
| title_sort | anticancer thiosemicarbazone triapine exerts immune enhancing activities via immunogenic cell death induction and fas upregulation |
| topic | Anticancer therapy Thiosemicarbazones Triapine Immunogenic cell death Immunomodulation Adaptive immune system |
| url | https://doi.org/10.1186/s40164-025-00700-0 |
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