A pH-responsive PROTAC-based nanosystem triggers tumor-specific ferroptosis to construct in situ tumor vaccines
Bromodomain-containing protein 4 (BRD4) is a key protein that drives the development of malignant melanoma and is closely associated with the ferroptosis signaling pathway. Degradation of BRD4 can downregulate the expression of ferroptosis-related genes such as GPX4, thereby promoting tumor-specific...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-04-01
|
| Series: | Materials Today Bio |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S259000642500081X |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832583094825123840 |
|---|---|
| author | Linghong Huang Xinyuan Sun Qinhua Zuo Ting Song Ning Liu Zonghua Liu Wei Xue |
| author_facet | Linghong Huang Xinyuan Sun Qinhua Zuo Ting Song Ning Liu Zonghua Liu Wei Xue |
| author_sort | Linghong Huang |
| collection | DOAJ |
| description | Bromodomain-containing protein 4 (BRD4) is a key protein that drives the development of malignant melanoma and is closely associated with the ferroptosis signaling pathway. Degradation of BRD4 can downregulate the expression of ferroptosis-related genes such as GPX4, thereby promoting tumor-specific ferroptosis. Therefore, targeting BRD4 for degradation is a promising strategy for inhibiting tumor growth. We constructed a PROTAC drug-based tumor antigen capture system to protect the activity of antigen-presenting cells (APCs) and promote antigen capture. The selected PROTAC drug (ARV-825) can specifically degrade BRD4 without harming immune cells. Specifically, magnetic nanoclusters (MNC) coated with calcium-doped manganese carbonate (Ca/MnCO3), were used to load PROTAC drug (ARV-825) and anti-PD1, forming the MNC@Ca/MnCO3/ARV/anti-PD1 system. ARV-825 can specifically degrade BRD4 and GPX4, significantly inducing ferroptosis in tumor cells and releasing tumor-associated antigens. The MNC@Ca/MnCO3 particles, with their large specific surface area, adsorbed the tumor antigens, preventing antigen loss and enhancing antigen presentation. Additionally, Mn2+ served as an adjuvant to promote the maturation and cross-presentation of APCs. Together with the PD1 antibody, this further enhanced the anti-tumor response of the in situ tumor vaccine and reversed the suppressive immune microenvironment. This antigen capture system provides a novel strategy to improve the anti-tumor efficacy of in situ tumor vaccines. |
| format | Article |
| id | doaj-art-74445e5f1498455cb05ad37786dfe718 |
| institution | Kabale University |
| issn | 2590-0064 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Materials Today Bio |
| spelling | doaj-art-74445e5f1498455cb05ad37786dfe7182025-01-29T05:01:40ZengElsevierMaterials Today Bio2590-00642025-04-0131101523A pH-responsive PROTAC-based nanosystem triggers tumor-specific ferroptosis to construct in situ tumor vaccinesLinghong Huang0Xinyuan Sun1Qinhua Zuo2Ting Song3Ning Liu4Zonghua Liu5Wei Xue6Department of Biomedical Engineering, Jinan University, Guangzhou, 510632, China; Department of Urology, Guangdong Provincial Key Laboratory of Urological Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510230, ChinaDepartment of Urology, Guangdong Provincial Key Laboratory of Urological Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510230, ChinaDepartment of Biomedical Engineering, Jinan University, Guangzhou, 510632, ChinaDepartment of Biomedical Engineering, Jinan University, Guangzhou, 510632, ChinaDepartment of Bone and Joint Surgery, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, 5106323, China; Corresponding author.Department of Biomedical Engineering, Jinan University, Guangzhou, 510632, China; Corresponding author.Department of Biomedical Engineering, Jinan University, Guangzhou, 510632, China; Corresponding author.Bromodomain-containing protein 4 (BRD4) is a key protein that drives the development of malignant melanoma and is closely associated with the ferroptosis signaling pathway. Degradation of BRD4 can downregulate the expression of ferroptosis-related genes such as GPX4, thereby promoting tumor-specific ferroptosis. Therefore, targeting BRD4 for degradation is a promising strategy for inhibiting tumor growth. We constructed a PROTAC drug-based tumor antigen capture system to protect the activity of antigen-presenting cells (APCs) and promote antigen capture. The selected PROTAC drug (ARV-825) can specifically degrade BRD4 without harming immune cells. Specifically, magnetic nanoclusters (MNC) coated with calcium-doped manganese carbonate (Ca/MnCO3), were used to load PROTAC drug (ARV-825) and anti-PD1, forming the MNC@Ca/MnCO3/ARV/anti-PD1 system. ARV-825 can specifically degrade BRD4 and GPX4, significantly inducing ferroptosis in tumor cells and releasing tumor-associated antigens. The MNC@Ca/MnCO3 particles, with their large specific surface area, adsorbed the tumor antigens, preventing antigen loss and enhancing antigen presentation. Additionally, Mn2+ served as an adjuvant to promote the maturation and cross-presentation of APCs. Together with the PD1 antibody, this further enhanced the anti-tumor response of the in situ tumor vaccine and reversed the suppressive immune microenvironment. This antigen capture system provides a novel strategy to improve the anti-tumor efficacy of in situ tumor vaccines.http://www.sciencedirect.com/science/article/pii/S259000642500081XIn situ tumor vaccinesAntigen presentationPROTACFerroptosis |
| spellingShingle | Linghong Huang Xinyuan Sun Qinhua Zuo Ting Song Ning Liu Zonghua Liu Wei Xue A pH-responsive PROTAC-based nanosystem triggers tumor-specific ferroptosis to construct in situ tumor vaccines Materials Today Bio In situ tumor vaccines Antigen presentation PROTAC Ferroptosis |
| title | A pH-responsive PROTAC-based nanosystem triggers tumor-specific ferroptosis to construct in situ tumor vaccines |
| title_full | A pH-responsive PROTAC-based nanosystem triggers tumor-specific ferroptosis to construct in situ tumor vaccines |
| title_fullStr | A pH-responsive PROTAC-based nanosystem triggers tumor-specific ferroptosis to construct in situ tumor vaccines |
| title_full_unstemmed | A pH-responsive PROTAC-based nanosystem triggers tumor-specific ferroptosis to construct in situ tumor vaccines |
| title_short | A pH-responsive PROTAC-based nanosystem triggers tumor-specific ferroptosis to construct in situ tumor vaccines |
| title_sort | ph responsive protac based nanosystem triggers tumor specific ferroptosis to construct in situ tumor vaccines |
| topic | In situ tumor vaccines Antigen presentation PROTAC Ferroptosis |
| url | http://www.sciencedirect.com/science/article/pii/S259000642500081X |
| work_keys_str_mv | AT linghonghuang aphresponsiveprotacbasednanosystemtriggerstumorspecificferroptosistoconstructinsitutumorvaccines AT xinyuansun aphresponsiveprotacbasednanosystemtriggerstumorspecificferroptosistoconstructinsitutumorvaccines AT qinhuazuo aphresponsiveprotacbasednanosystemtriggerstumorspecificferroptosistoconstructinsitutumorvaccines AT tingsong aphresponsiveprotacbasednanosystemtriggerstumorspecificferroptosistoconstructinsitutumorvaccines AT ningliu aphresponsiveprotacbasednanosystemtriggerstumorspecificferroptosistoconstructinsitutumorvaccines AT zonghualiu aphresponsiveprotacbasednanosystemtriggerstumorspecificferroptosistoconstructinsitutumorvaccines AT weixue aphresponsiveprotacbasednanosystemtriggerstumorspecificferroptosistoconstructinsitutumorvaccines AT linghonghuang phresponsiveprotacbasednanosystemtriggerstumorspecificferroptosistoconstructinsitutumorvaccines AT xinyuansun phresponsiveprotacbasednanosystemtriggerstumorspecificferroptosistoconstructinsitutumorvaccines AT qinhuazuo phresponsiveprotacbasednanosystemtriggerstumorspecificferroptosistoconstructinsitutumorvaccines AT tingsong phresponsiveprotacbasednanosystemtriggerstumorspecificferroptosistoconstructinsitutumorvaccines AT ningliu phresponsiveprotacbasednanosystemtriggerstumorspecificferroptosistoconstructinsitutumorvaccines AT zonghualiu phresponsiveprotacbasednanosystemtriggerstumorspecificferroptosistoconstructinsitutumorvaccines AT weixue phresponsiveprotacbasednanosystemtriggerstumorspecificferroptosistoconstructinsitutumorvaccines |