Sulfafurazole dimers potentiate chemo-immunotherapy of low immunogenic breast cancer by preventing the PD-L1 exosomes secretion.
10.1016/j.apsb.2025.03.007
- Author:
Zheng WANG
1
;
Ronghui YIN
1
;
Lin ZHANG
1
;
Shiyu LI
1
;
Zhanwei ZHOU
1
;
Minjie SUN
1
Author Information
1. NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
- Publication Type:Journal Article
- Keywords:
Breast cancer;
Carrier free nanomedicine;
Chemo-immunotherapy;
Exosomes depletion;
GSH responsive delivery system;
Immunogenic cell death;
Programmed death ligand 1;
T cells exhaustion
- From:
Acta Pharmaceutica Sinica B
2025;15(5):2673-2686
- CountryChina
- Language:English
-
Abstract:
The αPD-L1 antibody-based immune checkpoint blockade therapy is still limited by the poor clinical response rate as it is mainly utilized to block surface PD-L1 on tumor cells while ignoring abundant PD-L1 exosomes secreted in the environment, causing tumor immune evasion. Here, we proposed an exosome biogenesis inhibition strategy to suppress tumor exosomes secretion from the source, reducing the inhibitory effect on T cells and enhancing chemo-immunotherapy efficacy. We developed sulfafurazole homodimers (SAS) with disulfide linkages, effectively releasing the drug in response to glutathione (GSH) and inhibiting 4T1 tumor-derived exosomes secretion. Subsequently, gemcitabine (Gem) was encapsulated to induce immunogenic cell death (ICD). Consequently, Gem@SAS inhibited the secretion of tumor exosomes by more than 70%, increased proliferation and granzyme B secretion ability of T cells by more than 2 times, and showed superior efficacy in breast cancer treatment as well as lung metastasis of breast cancer.
