Endogenous Calcium-Supported dynamic Copper(II)-Crosslinked Gel depot for in situ disulfiram activation and synergistic cancer therapy

The development of smart therapeutic scaffolds to improve chemotherapeutic efficacy and enhance antitumor immunity remains a considerable challenge. In this study, we engineered a therapeutic copper ion-crosslinked gel depot based on alginate to enhance disulfiram (DSF)-mediated cancer chemoimmunotherapy. This gel depot maintained structural stability through ion coordination exchange with the calcium ions in body fluids and continuously created an antitumor diethyldithiocarbamate-copper complex (CuET), which led to the sustained release of various therapeutic agents in vivo. The generated CuET not only had a direct antitumor effect due to its cytotoxicity but also effectively induced the immunogenic death of cancer cells. These factors coregulated the immunosuppressed tumor microenvironment with the released DSF, thus sensitizing the systemic immune response and improving the efficacy of anti-programmed cell death-ligand 1 antibody (aPD-L1)-mediated immune checkpoint blockade. The results indicated that this endogenous calcium-supported therapeutic copper(II)-crosslinked gel depot could effectively improve the tumor immune microenvironment, leading to enhanced synergistic antitumor efficacy in vivo.