Cuproptosis, a recently identified form of copper-dependent cell death, shows promising tumor suppressive effects with minimal drug resistance. However, its therapeutic efficacy is hampered by its dependence on copper ions and the glutathione (GSH)-rich microenvironment in tumors. Here, we have developed polyvalent aptamer nanodrug conjugates (termed CuPEs@PApt) with a nucleosome-like structure to improve tumor cuproptosis therapy by exploiting mitochondrial copper overload and GSH depletion. Polyvalent aptamer (PApt), comprising polyvalent epithelial cell adhesion molecule aptamers for tumor targeting and repetitive PolyT sequences for copper chelation, facilitates efficient loading and targeted delivery of copper peroxide-Elesclomol nanodots (CuPEs). Upon internalization by tumor cells, Elesclomol released from CuPEs@PApt accumulates copper ions in mitochondria to initiate cuproptosis, while lysosomal degradation of CuP nanodots generates exogenous Cu2+ and H2O2, triggering a Fenton-like reaction for GSH depletion to enhance cuproptosis. In vitro and in vivo experiments confirm the efficacy of this strategy in inducing tumor cell cuproptosis and immunogenic cell death, the latter contributing to the activation of the antitumor immune response for synergistic tumor growth inhibition.