Tumor microenvironment-reprogrammable CpG-templated copper sulfide loaded with disulfiram for sensitized cuproptosis immunotherapy

Cuproptosis synergized with immunogenic cell death (ICD) triggered immunotherapy offers huge potential in addressing the limitations of current tumor therapies. However, the sensitivity of cuproptosis immunotherapy is severely restricted by multiple resistances derived from tumor microenvironment (TME). Herein, the Toll-like receptor agonist CpG templated copper sulfide loaded with disulfiram (DSF/CuS-C) was designed as a TME-reprogrammable cuproptosis nanoinducer for sensitizing tumor cell cuproptosis and simultaneously augmenting ICD driven anti-tumor immunity. The initiation of a sensitized cuproptosis via DSF/CuS-C mediated repolarization of M2 phenotypic macrophages with an assistant with photothermal effect was evidenced by the increased level of aggregation of lipoylated mitochondrial proteins and proteotoxic stress, which eventually resulted in a robust anti-tumor immune response for effectively eradating the breast tumor on a mouse model. The TME activated cuproptosis nanoinducer thus represents a novel and effective strategy for cooperatively reinforcing cuproptosis and anti-tumor immune response, holding great promise for innovation in the field of breast cancer treatment.