A Polymeric Hydrogel to Eliminate Programmed Death-Ligand 1 for Enhanced Tumor Radio-Immunotherapy

Programmed death-ligand 1 (PD-L1) is a specialized shield on tumor cells that evades the immune system. Even inhibited by PD-L1 antibodies, a cycling process constantly transports PD-L1 from inside to outside of cells, facilitating the renewal and replenishment of PD-L1 on the cancer cell membrane....

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Bibliographic Details
Published in:ACS nano 2023-12, Vol.17 (23), p.23998-24011
Main Authors: Shen, Wenhao, Pei, Pei, Zhang, Chonghai, Li, Junmei, Han, Xiangming, Liu, Teng, Shi, Xiumin, Su, Zhiyue, Han, Gaohua, Hu, Lin, Yang, Kai
Format: Article
Language:English
Subjects:
Alginates
Animals
B7-H1 Antigen
Colonic Neoplasms - drug therapy
Copper
Galactose
Hydrogels
Immunotherapy - methods
Ions
Ligands
Mice
Tumor Microenvironment
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Summary:Programmed death-ligand 1 (PD-L1) is a specialized shield on tumor cells that evades the immune system. Even inhibited by PD-L1 antibodies, a cycling process constantly transports PD-L1 from inside to outside of cells, facilitating the renewal and replenishment of PD-L1 on the cancer cell membrane. Herein, we develop a sodium alginate hydrogel consisting of elesclomol-Cu and galactose to induce persistent cuproptosis, leading to the reduction of PD-L1 for radio-immunotherapy of colon tumors. First, a prefabricated hydrogel is synthesized by immobilizing elesclomol onto a sodium alginate saccharide chain through the coordination with bivalent copper ions (Cu2+), followed by incorporation of galactose. After implantation into the tumors, this prefabricated hydrogel can be further cross-linked in the presence of physiological calcium ions (Ca2+), resulting in the formation of a hydrogel with controlled release of elesclomol-Cu2+ (ES-Cu) and galactose. The hydrogel effectively induces the oligomerization of DLAT and cuproptosis in colorectal cancer cells. Interestingly, radiation-induced PD-L1 upregulation is abrogated in the presence of the hydrogel, releasing ES-Cu and galactose. Consequently, the sensitization of tumor to radiotherapy and immunotherapy is significantly improved, further prolonging the survival of tumor-bearing mice in both local and metastatic tumors. Our study introduces an approach that combines cuproptosis with immunotherapy and radiotherapy.
ISSN:1936-0851
1936-086X
DOI:10.1021/acsnano.3c08875