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!
|
| Summary: | 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. |
|---|---|
| ISSN: | 2590-0064 |