Copper induces antitumor immune responses by triggering cuproptosis and immunogenic cell death

Immunotherapy has improved the treatment of non-small cell lung cancer (NSCLC), but its efficacy remains limited by the immunosuppressive tumor microenvironment. Although copper has recently emerged as a potential anticancer target, its role in tumor immunity remains unclear. In this study, we investigated the effects of Cu²⁺ on tumor immunity and its impact on PD-L1 blockade therapy. Cu²⁺ significantly inhibited NSCLC growth in vitro and in vivo without causing obvious systemic toxicity. Mechanistically, Cu²⁺ induced cuproptosis, accompanied by metabolic alterations and cuproptosis-associated molecular changes. Importantly, Cu²⁺ treatment triggered immunogenic cell death (ICD), as evidenced by increased calreticulin exposure and enhanced ATP and HMGB1 release. Pharmacological inhibition of cuproptosis attenuated these ICD-associated responses, supporting a mechanistic link between cuproptosis and ICD. In vivo, Cu²⁺ treatment promoted dendritic cell maturation, increased CD4⁺ and CD8⁺ T-cell infiltration, reduced myeloid-derived suppressor cell accumulation, and facilitated macrophage polarization toward a pro-inflammatory phenotype. Furthermore, Cu²⁺ significantly enhanced the antitumor efficacy of PD-L1 blockade. These findings demonstrate that Cu²⁺ promotes antitumor immunity through a cuproptosis-associated ICD pathway and improves responsiveness to PD-L1 blockade. Targeting copper homeostasis may represent a potential strategy for enhancing immunotherapy efficacy in NSCLC.