Cuprous oxide nanocomposites with photothermal (PTT) and chemical dynamics (CDT) effects induce cuproptosis in breast cancer using the strategy of increasing inflow and reducing outflow

Chemotherapy is a crucial adjuvant method of treating breast cancer, but it fails to achieve preferable prognosis as the malignant cells eventually develop drug-resistance. Reduced chemotherapeutic sensitivity is primarily caused by endogenous and exogenous resistance during the treatment. Cuproptosis is a newly discovered immunogenic cell death (ICD), characterized by accumulation of copper (Cu) ions inside tumor cells. However, intracellular Cu ion concentrations can hardly reach desired levels to induce cuproptosis due to limited import via existing Cu ionophores and synchronous export via ATP-Cu pump. Herein, our research developed an elesclomol (ES) loaded cuprous oxide (Cu2O) nanocomposite, called PEG@Cu2O-ES, to solve this dilemma. Our designed PEG@Cu2O-ES could efficiently enter the breast cancer cells, release encapsulated ES and Cu2O, while the photothermal (PTT) effect of Cu2O induced by near-infrared II region (NIR-II) radiation could in turn accelerate the releasing process. Cu2O discharged substantial amounts of Cu in cytoplasm, which directly engaged in the tricarboxylic acid (TCA) cycle in mitochondria, resulting in cuproptosis to some extent. As a result of PTT-enhanced Fenton-like reactions, Cu2O generated a substantial quantity of reactive oxygen species (ROS) that attacked the ATP-Cu pump on cancer cells' membranes, thereby reducing the outflow of Cu ions and aggravating cuproptosis. Additionally, free ES further promoted Cu from the tumor microenvironment (TME) to enter breast cancer cells, and exacerbated cuproptosis with higher efficiency. In vivo, PEG@Cu2O-ES nanocomposites showed strong anti-tumor effect by inducing cuproptosis, as well as the ability to reprogram the TME and increase the response-sensitivity to programmed cell death protein-1 antibody (αPD-1). In conclusion, this study provides a promising strategy by combining a nano-drug with αPD-1 for sensitizing immunotherapy of chemotherapy-resistant breast cancer.