Restoration of the Immunogenicity of Tumor Cells for Enhanced Cancer Therapy via Nanoparticle‐Mediated Copper Chaperone Inhibition

Abstract Recent progress in studying copper‐dependent targets and pathways in the context of tumor treatment has provided new insights into therapeutic strategies of leveraging copper‐dependent disease vulnerabilities and pharmacological manipulation of intratumor copper transportation to improve chemotherapy. Here, we developed reactive oxygen species (ROS)‐sensitive nanoparticles loaded with copper chaperone inhibitor DC_AC50 and cisplatin(IV) prodrug. The released DC_AC50 can promote a remarkable accumulation of intracellular cisplatin and copper through inhibition of the Atox1‐ATPase pathways, thereby enhancing the chemotherapeutic effect of cisplatin and inducing significant ROS generation. Excessive ROS then elicits intense endoplasmic reticulin (ER) stress which facilitates the immunogenic cell death (ICD) spurring a sustained immune response. Our study suggests that nanoparticle‐mediated copper chaperone inhibition via DC_AC50 can restore the immunogenicity of tumor cells for enhanced chemotherapy and cancer immunotherapy.