Mitochondria‐Targeting Nanocuproptosis Breaks Immune Resistance

ABSTRACT Cuproptosis, an emerging form of mitochondrial cell death triggered by copper overload, has attracted increasing attention in tumor therapy. However, clinically available copper delivery agents lack tumor mitochondrial targeting specificity, which markedly restricts their clinical application due to their possible hepatotoxicity and nephrotoxicity. Here, we design a stepwise‐targeted nanocuproptosis (MTPY‐Cu@Alb), capable of sequentially targeting both tumor mitochondria to selectively induce cuproptosis. Strikingly, MTPY‐Cu@Alb triggers nanocuproptosis at only 1/1000 the dosage of free copper ions, which then simultaneously reverses tumor immune tolerance mediated by copper homeostasis. Mechanistically, MTPY‐Cu@Alb precisely induces cuproptosis and downregulates the immune checkpoints Cluster of Differentiation 276 (CD276) and Cluster of Differentiation 47 (CD47). By reducing these immune checkpoints, MTPY‐Cu@Alb effectively reverses adaptive (CD276‐associated) and innate (CD47‐associated) immune resistance, thereby promoting T‐cell infiltration, enhancing cytotoxic activity, and increasing macrophage phagocytosis of tumor cells. Functionally, MTPY‐Cu@Alb‐induced nanocuproptosis not only exhibits potent antitumor efficacy but also overcomes the chemotherapy‐induced upregulation of immune checkpoints and disrupts chemotherapy‐mediated resistance to cuproptosis, thereby achieving synergistic antitumor activity with chemotherapy. Collectively, this work highlights the potent ability of using MTPY‐Cu@Alb as a promising mitochondria‐targeted nanocuproptosis to reverse tumor immune resistance by inhibiting CD276 and CD47 expression and enhancing responsiveness to chemotherapy.