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 Cu 2+ on tumor immunity and its impact on PD-L1 blockade therapy. Cu 2+ significantly inhibited NSCLC growth in vitro and in vivo without causing obvious systemic toxicity. Mechanistically, Cu 2+ induced cuproptosis, accompanied by metabolic alterations and cuproptosis-associated molecular changes. Importantly, Cu 2+ 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, Cu 2+ 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, Cu 2+ significantly enhanced the antitumor efficacy of PD-L1 blockade. These findings demonstrate that Cu 2+ 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. Download: Download high-res image (470KB) Download: Download full-size image