Photothermal therapy combined with a STING agonist induces pyroptosis, and gasdermin D could be a new biomarker for guiding the treatment of pancreatic cancer
Abstract Purpose Although photothermal therapy (PTT) can induce antitumour immunity, the mechanisms underlying its effects in pancreatic cancer (PC) require further exploration. In this study, the mechanism of action of PTT and its connection to pyroptosis as well as the therapeutic potential of PTT...
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| Language: | English |
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BMC
2025-03-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06247-2 |
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| author | Yanyan Hu ErPeng Qi Chao Yun Xi Li Fangyi Liu Zhigang Cheng Na Guan Qiong Wang Huixia Zhao Wenhua Xiao Liang Peng Jingwen Yang Xiaoling Yu |
| author_facet | Yanyan Hu ErPeng Qi Chao Yun Xi Li Fangyi Liu Zhigang Cheng Na Guan Qiong Wang Huixia Zhao Wenhua Xiao Liang Peng Jingwen Yang Xiaoling Yu |
| author_sort | Yanyan Hu |
| collection | DOAJ |
| description | Abstract Purpose Although photothermal therapy (PTT) can induce antitumour immunity, the mechanisms underlying its effects in pancreatic cancer (PC) require further exploration. In this study, the mechanism of action of PTT and its connection to pyroptosis as well as the therapeutic potential of PTT alone and in combination with STING agonists, were investigated. In addition, a biomarker of PC was found to stratify patients who are suitable for PTT. Experimental design We explored whether PTT can induce pyroptosis in vitro and evaluated the therapeutic efficacy and antitumour immunity-inducing ability of PTT combined with STING agonist (c-di-GMP) as immune adjuvant in vivo in PC. We also evaluated gasdermin D (GSDMD) expression in tumour tissues and investigated drug sensitivity in patient-derived organoids (PDOs) with differential GSDMD expression. Results Our study demonstrated that local PTT induces pyroptosis via the caspase-1/GSDMD pathway and elicits antitumour immunity. PTT combined with a STING agonist exhibits better therapeutic efficacy than PTT alone while limiting distant tumour metastasis, and enhances the immune response by promoting dendritic cell maturation, increasing the frequency of tumour infiltrating T cells, and converting macrophages from the M2 to the M1 phenotype. In addition, we found that GSDMD is highly expressed in tumour tissues and that overexpression of GSDMD in PC might suggest increased resistance to chemotherapy and the potential benefits of local therapy. We further confirmed that PDOs with higher GSDMD expression are less sensitive to a chemotherapeutic agent (5-Fluorouracil) than PDOs with lower GSDMD expression, making GSDMD a new biomarker for identifying patients who may benefit from PTT. Conclusions In this work, c-di-GMP was used as an immune adjuvant for PTT to treat PC for the first time, and the results provide clues for the development of novel combination immunotherapies that simultaneously suppress primary tumours and distant metastases. GSDMD has great potential as a new biomarker for the selection of individualized treatment modalities. |
| format | Article |
| id | doaj-art-02fbb5694df94e0ca9bcb9646b811c67 |
| institution | DOAJ |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-02fbb5694df94e0ca9bcb9646b811c672025-08-20T03:05:44ZengBMCJournal of Translational Medicine1479-58762025-03-0123111810.1186/s12967-025-06247-2Photothermal therapy combined with a STING agonist induces pyroptosis, and gasdermin D could be a new biomarker for guiding the treatment of pancreatic cancerYanyan Hu0ErPeng Qi1Chao Yun2Xi Li3Fangyi Liu4Zhigang Cheng5Na Guan6Qiong Wang7Huixia Zhao8Wenhua Xiao9Liang Peng10Jingwen Yang11Xiaoling Yu12Department of Oncology, Senior Department of Oncology, the Fifth Medical Center of PLA General HospitalDepartment of Interventional Ultrasound, Senior Department of Oncology, The Fifth Medical Center of PLA General HospitalDepartment of Oncology, Senior Department of Oncology, the Fifth Medical Center of PLA General HospitalDepartment of Urology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS FoundationDepartment of Interventional Ultrasound, Senior Department of Oncology, The Fifth Medical Center of PLA General HospitalDepartment of Interventional Ultrasound, Senior Department of Oncology, The Fifth Medical Center of PLA General HospitalDepartment of Oncology, Senior Department of Oncology, the Fifth Medical Center of PLA General HospitalDepartment of Ultrasound, the Fourth Medical Center of PLA General HospitalDepartment of Oncology, Senior Department of Oncology, the Fifth Medical Center of PLA General HospitalDepartment of Oncology, Senior Department of Oncology, the Fifth Medical Center of PLA General HospitalDepartment of Oncology, Senior Department of Oncology, the Fifth Medical Center of PLA General HospitalDepartment of Oncology, Senior Department of Oncology, the Fifth Medical Center of PLA General HospitalDepartment of Interventional Ultrasound, Senior Department of Oncology, The Fifth Medical Center of PLA General HospitalAbstract Purpose Although photothermal therapy (PTT) can induce antitumour immunity, the mechanisms underlying its effects in pancreatic cancer (PC) require further exploration. In this study, the mechanism of action of PTT and its connection to pyroptosis as well as the therapeutic potential of PTT alone and in combination with STING agonists, were investigated. In addition, a biomarker of PC was found to stratify patients who are suitable for PTT. Experimental design We explored whether PTT can induce pyroptosis in vitro and evaluated the therapeutic efficacy and antitumour immunity-inducing ability of PTT combined with STING agonist (c-di-GMP) as immune adjuvant in vivo in PC. We also evaluated gasdermin D (GSDMD) expression in tumour tissues and investigated drug sensitivity in patient-derived organoids (PDOs) with differential GSDMD expression. Results Our study demonstrated that local PTT induces pyroptosis via the caspase-1/GSDMD pathway and elicits antitumour immunity. PTT combined with a STING agonist exhibits better therapeutic efficacy than PTT alone while limiting distant tumour metastasis, and enhances the immune response by promoting dendritic cell maturation, increasing the frequency of tumour infiltrating T cells, and converting macrophages from the M2 to the M1 phenotype. In addition, we found that GSDMD is highly expressed in tumour tissues and that overexpression of GSDMD in PC might suggest increased resistance to chemotherapy and the potential benefits of local therapy. We further confirmed that PDOs with higher GSDMD expression are less sensitive to a chemotherapeutic agent (5-Fluorouracil) than PDOs with lower GSDMD expression, making GSDMD a new biomarker for identifying patients who may benefit from PTT. Conclusions In this work, c-di-GMP was used as an immune adjuvant for PTT to treat PC for the first time, and the results provide clues for the development of novel combination immunotherapies that simultaneously suppress primary tumours and distant metastases. GSDMD has great potential as a new biomarker for the selection of individualized treatment modalities.https://doi.org/10.1186/s12967-025-06247-2PyroptosisPhotothermal therapyPancreatic cancerSTING agonistGSDMD |
| spellingShingle | Yanyan Hu ErPeng Qi Chao Yun Xi Li Fangyi Liu Zhigang Cheng Na Guan Qiong Wang Huixia Zhao Wenhua Xiao Liang Peng Jingwen Yang Xiaoling Yu Photothermal therapy combined with a STING agonist induces pyroptosis, and gasdermin D could be a new biomarker for guiding the treatment of pancreatic cancer Journal of Translational Medicine Pyroptosis Photothermal therapy Pancreatic cancer STING agonist GSDMD |
| title | Photothermal therapy combined with a STING agonist induces pyroptosis, and gasdermin D could be a new biomarker for guiding the treatment of pancreatic cancer |
| title_full | Photothermal therapy combined with a STING agonist induces pyroptosis, and gasdermin D could be a new biomarker for guiding the treatment of pancreatic cancer |
| title_fullStr | Photothermal therapy combined with a STING agonist induces pyroptosis, and gasdermin D could be a new biomarker for guiding the treatment of pancreatic cancer |
| title_full_unstemmed | Photothermal therapy combined with a STING agonist induces pyroptosis, and gasdermin D could be a new biomarker for guiding the treatment of pancreatic cancer |
| title_short | Photothermal therapy combined with a STING agonist induces pyroptosis, and gasdermin D could be a new biomarker for guiding the treatment of pancreatic cancer |
| title_sort | photothermal therapy combined with a sting agonist induces pyroptosis and gasdermin d could be a new biomarker for guiding the treatment of pancreatic cancer |
| topic | Pyroptosis Photothermal therapy Pancreatic cancer STING agonist GSDMD |
| url | https://doi.org/10.1186/s12967-025-06247-2 |
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