Bimetallic nanoplatform inducing robust cuproptosis to enhance tumor immunotherapy via immunogenic activation and tumor microenvironment reprogramming

Cuproptosis, a novel copper-dependent cell death mechanism distinct from apoptosis, offers potential breakthroughs in overcoming resistance to conventional tumor therapies. Current challenges include the safe delivery of adequate copper concentrations, selective targeting to tumor cells, potential resistance development, and overcoming immunosuppressive tumor environments. We introduce a synergistic approach using an near-infrared (NIR)-II activatable bimetallic nanoplatform, termed APDC, which integrates cuproptosis with immunotherapy. In this design, copper ions (Cu 2+ ) and disulfiram (DSF) are sequestered within the nanoplatforms by lauric acid (LA), ensuring stability until NIR-II irradiation. Upon NIR-II irradiation, APDC's photothermal properties melt LA, releasing Cu 2+ and DSF which react to form cytotoxic bis(diethyldithiocarbamate)copper complex (CuET) and cuprous ions (Cu + ), facilitating effective cuproptosis and apoptosis. In vivo studies reveal that APDC under NIR-II light not only significantly curtails tumor growth compared to monotherapies but also triggers strong antigen-presentation response and immunosuppression reprogramming. This effects includes dendritic cell maturation, heightened infiltration of cytotoxic T lymphocytes, and activation of memory T cells, and effectively converting immunologically “cold” tumors into responsive “hot” tumors, collectively inhibiting both primary and distant tumors in squamous cell carcinoma models. Our findings show the potential of NIR-II activated nanomedicines in cuproptosis-based immunotherapy as advanced tumor treatment strategy. • A near-infrared (NIR)-II activatable bimetallic nanoplatform, APDC, that synergistically combines cuproptosis with immunotherapy, offering a targeted approach to combat drug-resistant bacterial infections in tumor therapy. • APDC utilizes photothermal effects to release copper ions and disulfiram, inducing cuproptosis and apoptosis simultaneously, significantly amplifying the immune response against tumors. • APDC under NIR-II light not only significantly halts tumor growth but also reprograms the immunosuppressive tumor environment, promoting dendritic cell maturation and cytotoxic T lymphocyte infiltration, effectively converting ‘cold’ tumors into ‘hot’ tumors. • Highlights the potential of APDC as a comprehensive tumor treatment strategy that could reshape the landscape of cancer immunotherapy, providing a new pathway for effectively managing squamous cell carcinoma and potentially other cancer types