Cage‐Like Nanodrug Potentiates Tumor Immunotherapy by Orchestrating Endoplasmic Reticulum–Mitochondrial Crosstalk

ABSTRACT Ion homeostasis disruption offers potential for antitumor immunity, but its therapeutic efficacy remains unsatisfactory owing to the difficulty in eliciting robust immunogenicity and the ambiguous underlying molecular mechanisms. Here, we present a tumor‐targeted cage‐like nanodrug (CuCa‐EB‐H), hyaluronan‐decorated proteasome inhibitor bortezomib (BTZ)/copper ionophore elesclomol (ES)‐loaded copper‐calcium bimetallic nanocages, for unlocking the mechanisms of orchestrating endoplasmic reticulum (ER) stress and mitochondrial dysfunction to induce antitumor immunity. Specifically, BTZ and exogenous Ca 2 ⁺ overload provoke ER stress, which not only induces the transposition of ER calreticulin on the cell surface but also triggers massive endogenous Ca 2+ efflux and transmission into mitochondria to aggravate mitochondrial Ca 2+ overload. Synchronously, ES mediates the targeting delivery and accumulation of Cu 2+ in mitochondria to induce cuproptosis, which further exacerbates mitochondrial injury and promotes mtDNA release, thus activating the cGAS–STING pathway and ensuing ER stress‐mediated antitumor immunity. Furthermore, cuproptosis synergizes with these processes to amplify damage‐associated molecular patterns release, manifesting robust immunogenic effect. Collectively, the CuCa‐EB‐H nanodrug establishes a reciprocal ER stress‐mitochondrial dysfunction‐STING activation self‐reinforcing cascade that markedly stimulates dendritic cell maturation, increases effector T cell infiltration, and reverses immunosuppressive tumor microenvironment. This study provides mechanistic insights into ion interference immunotherapy and a promising strategy to strengthen immune checkpoint therapy.