GRP78 Nanobody‐Directed Immunotoxin Activates Innate Immunity Through STING Pathway to Synergize Tumor Immunotherapy
Abstract The lack of targetable antigens poses a significant challenge in developing effective cancer‐targeted therapies. Cell surface translocation of endoplasmic reticulum (ER) chaperones, such as glucose‐regulated protein 78 (GRP78), during malignancy, drug resistance, and ER stress induced by th...
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Wiley
2025-05-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202408086 |
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| author | Huifang Wang Runhua Zhou Chengchao Xu Lingyun Dai Rui Hou Liuhai Zheng Chunjin Fu Guangwei Shi Jingwei Wang Yang Li Jinpeng Cen Xiaolong Xu Le Yu Yilei Li Jigang Wang Qingfeng Du Zhijie Li |
| author_facet | Huifang Wang Runhua Zhou Chengchao Xu Lingyun Dai Rui Hou Liuhai Zheng Chunjin Fu Guangwei Shi Jingwei Wang Yang Li Jinpeng Cen Xiaolong Xu Le Yu Yilei Li Jigang Wang Qingfeng Du Zhijie Li |
| author_sort | Huifang Wang |
| collection | DOAJ |
| description | Abstract The lack of targetable antigens poses a significant challenge in developing effective cancer‐targeted therapies. Cell surface translocation of endoplasmic reticulum (ER) chaperones, such as glucose‐regulated protein 78 (GRP78), during malignancy, drug resistance, and ER stress induced by therapies, offers a promising pan‐cancer target. To target GRP78, nanobody C5, identified from a phage library and exhibiting high affinity for human and mouse GRP78, is utilized to develop the Pseudomonas exotoxin (PE) immunotoxin C5‐PE38. C5‐PE38 induced ER stress, apoptosis and immunogenic cell death in targeted cells and showed antitumor efficacy against colorectal cancer and melanoma models without obvious toxicity. Mechanistically, transcriptome profiling showed that C5‐PE38 reshaped the tumor immune microenvironment with enhanced innate and adaptive immune response and response to interferon beta. Moreover, C5‐PE38‐induced cell death could trans‐activate STING pathway in dendritic cells and macrophages, promoting CD8+ T cell infiltration. It also sensitizes both primary and metastatic melanomas to anti‐PD1 therapy, partly through STING activation. Overall, this study unveils a feasible GRP78 nanobody‐directed therapy strategy for single or combinatorial cancer intervention. This work finds that C5‐PE38‐induced cell death stimulates STING‐dependent cytosolic DNA release to promote antitumor immunity, a mechanism not previously reported for PE38, providing valuable insights for its clinical use. |
| format | Article |
| id | doaj-art-45b5d98db04d4372ab2bcd47d05dc111 |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-45b5d98db04d4372ab2bcd47d05dc1112025-08-20T03:13:30ZengWileyAdvanced Science2198-38442025-05-011219n/an/a10.1002/advs.202408086GRP78 Nanobody‐Directed Immunotoxin Activates Innate Immunity Through STING Pathway to Synergize Tumor ImmunotherapyHuifang Wang0Runhua Zhou1Chengchao Xu2Lingyun Dai3Rui Hou4Liuhai Zheng5Chunjin Fu6Guangwei Shi7Jingwei Wang8Yang Li9Jinpeng Cen10Xiaolong Xu11Le Yu12Yilei Li13Jigang Wang14Qingfeng Du15Zhijie Li16Department of Critical Care Medicine Guangdong Provincial Clinical Research Center for Geriatrics Shenzhen Clinical Research Centre for Geriatrics Department of Nuclear Medicine Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical CollegeJinan University) Shenzhen Guangdong 518020 ChinaClinical Pharmacy Center Nanfang Hospital Southern Medical University Guangzhou Guangdong 510515 ChinaDepartment of Critical Care Medicine Guangdong Provincial Clinical Research Center for Geriatrics Shenzhen Clinical Research Centre for Geriatrics Department of Nuclear Medicine Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical CollegeJinan University) Shenzhen Guangdong 518020 ChinaDepartment of Critical Care Medicine Guangdong Provincial Clinical Research Center for Geriatrics Shenzhen Clinical Research Centre for Geriatrics Department of Nuclear Medicine Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical CollegeJinan University) Shenzhen Guangdong 518020 ChinaDepartment of Critical Care Medicine Guangdong Provincial Clinical Research Center for Geriatrics Shenzhen Clinical Research Centre for Geriatrics Department of Nuclear Medicine Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical CollegeJinan University) Shenzhen Guangdong 518020 ChinaDepartment of Critical Care Medicine Guangdong Provincial Clinical Research Center for Geriatrics Shenzhen Clinical Research Centre for Geriatrics Department of Nuclear Medicine Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical CollegeJinan University) Shenzhen Guangdong 518020 ChinaDepartment of Critical Care Medicine Guangdong Provincial Clinical Research Center for Geriatrics Shenzhen Clinical Research Centre for Geriatrics Department of Nuclear Medicine Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical CollegeJinan University) Shenzhen Guangdong 518020 ChinaDepartment of Neurosurgery & Medical Research Center Shunde Hospital Southern Medical University (The First People's Hospital of Shunde Foshan) Guangzhou 510515 ChinaDepartment of Critical Care Medicine Guangdong Provincial Clinical Research Center for Geriatrics Shenzhen Clinical Research Centre for Geriatrics Department of Nuclear Medicine Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical CollegeJinan University) Shenzhen Guangdong 518020 ChinaDepartment of Critical Care Medicine Guangdong Provincial Clinical Research Center for Geriatrics Shenzhen Clinical Research Centre for Geriatrics Department of Nuclear Medicine Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical CollegeJinan University) Shenzhen Guangdong 518020 ChinaDepartment of Urology Nanfang Hospital Southern Medical University Guangzhou Guangdong 510515 ChinaDepartment of Critical Care Medicine Guangdong Provincial Clinical Research Center for Geriatrics Shenzhen Clinical Research Centre for Geriatrics Department of Nuclear Medicine Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical CollegeJinan University) Shenzhen Guangdong 518020 ChinaClinical Pharmacy Center Nanfang Hospital Southern Medical University Guangzhou Guangdong 510515 ChinaClinical Pharmacy Center Nanfang Hospital Southern Medical University Guangzhou Guangdong 510515 ChinaSchool of Traditional Chinese Medicine and School of Pharmaceutical Sciences Guangdong Provincial Key Laboratory of New Drug Screening School of Pharmaceutical Sciences Southern Medical University Guangzhou Guangdong 510515 ChinaSchool of Traditional Chinese Medicine and School of Pharmaceutical Sciences Guangdong Provincial Key Laboratory of New Drug Screening School of Pharmaceutical Sciences Southern Medical University Guangzhou Guangdong 510515 ChinaDepartment of Critical Care Medicine Guangdong Provincial Clinical Research Center for Geriatrics Shenzhen Clinical Research Centre for Geriatrics Department of Nuclear Medicine Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical CollegeJinan University) Shenzhen Guangdong 518020 ChinaAbstract The lack of targetable antigens poses a significant challenge in developing effective cancer‐targeted therapies. Cell surface translocation of endoplasmic reticulum (ER) chaperones, such as glucose‐regulated protein 78 (GRP78), during malignancy, drug resistance, and ER stress induced by therapies, offers a promising pan‐cancer target. To target GRP78, nanobody C5, identified from a phage library and exhibiting high affinity for human and mouse GRP78, is utilized to develop the Pseudomonas exotoxin (PE) immunotoxin C5‐PE38. C5‐PE38 induced ER stress, apoptosis and immunogenic cell death in targeted cells and showed antitumor efficacy against colorectal cancer and melanoma models without obvious toxicity. Mechanistically, transcriptome profiling showed that C5‐PE38 reshaped the tumor immune microenvironment with enhanced innate and adaptive immune response and response to interferon beta. Moreover, C5‐PE38‐induced cell death could trans‐activate STING pathway in dendritic cells and macrophages, promoting CD8+ T cell infiltration. It also sensitizes both primary and metastatic melanomas to anti‐PD1 therapy, partly through STING activation. Overall, this study unveils a feasible GRP78 nanobody‐directed therapy strategy for single or combinatorial cancer intervention. This work finds that C5‐PE38‐induced cell death stimulates STING‐dependent cytosolic DNA release to promote antitumor immunity, a mechanism not previously reported for PE38, providing valuable insights for its clinical use.https://doi.org/10.1002/advs.202408086cell surface glucose‐regulated protein 78 (GRP78)immunotherapyimmunotoxinSTING pathwaytargeted therapy |
| spellingShingle | Huifang Wang Runhua Zhou Chengchao Xu Lingyun Dai Rui Hou Liuhai Zheng Chunjin Fu Guangwei Shi Jingwei Wang Yang Li Jinpeng Cen Xiaolong Xu Le Yu Yilei Li Jigang Wang Qingfeng Du Zhijie Li GRP78 Nanobody‐Directed Immunotoxin Activates Innate Immunity Through STING Pathway to Synergize Tumor Immunotherapy Advanced Science cell surface glucose‐regulated protein 78 (GRP78) immunotherapy immunotoxin STING pathway targeted therapy |
| title | GRP78 Nanobody‐Directed Immunotoxin Activates Innate Immunity Through STING Pathway to Synergize Tumor Immunotherapy |
| title_full | GRP78 Nanobody‐Directed Immunotoxin Activates Innate Immunity Through STING Pathway to Synergize Tumor Immunotherapy |
| title_fullStr | GRP78 Nanobody‐Directed Immunotoxin Activates Innate Immunity Through STING Pathway to Synergize Tumor Immunotherapy |
| title_full_unstemmed | GRP78 Nanobody‐Directed Immunotoxin Activates Innate Immunity Through STING Pathway to Synergize Tumor Immunotherapy |
| title_short | GRP78 Nanobody‐Directed Immunotoxin Activates Innate Immunity Through STING Pathway to Synergize Tumor Immunotherapy |
| title_sort | grp78 nanobody directed immunotoxin activates innate immunity through sting pathway to synergize tumor immunotherapy |
| topic | cell surface glucose‐regulated protein 78 (GRP78) immunotherapy immunotoxin STING pathway targeted therapy |
| url | https://doi.org/10.1002/advs.202408086 |
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