Transition-metal nanocatalysis represents a novel alternative currently experiencing flourishing progress to tackle the tumor microenvironment (TME) in cancer therapy. These nanomaterials aim at attacking tumor cells using the intrinsic selectivity of inorganic catalysts. In addition, special attention to tune and control the release of these transition metals is also required. Understanding the chemical reactions behind the catalytic action of the transition-metal nanocatalysts and preventing potential undesired side reactions caused by acute cytotoxicity of the released ionic species represent another important field of research. Specifically, copper-based oxides may suffer from acute leaching that potentially may induce toxicity not only to target cancer cells but also to nearby cells and tissues. In this work, we propose the synthesis of chalcopyrite (CuFeS2) nanostructures capable of triggering two key reactions for an effective chemodynamic therapy (CDT) in the heterogeneous phase: (i) glutathione (GSH) oxidation and (ii) oxidation of organic substrates using H2O2, with negligible leaching of metals under TME-like conditions. This represents an appealing alternative toward the development of safer copper-iron-based nanocatalytic materials with an active catalytic response without incurring leaching side phenomena.