Cuproptosis meets sonodynamics: a nanomedicine platform for multimodal cancer therapy

Cancer treatment is shifting beyond the traditional single-agent therapy. The focus of research has shifted to combination strategies that target specific metabolic dependencies in the tumor microenvironment (TME). Recently, cuproptosis has been characterized as a type of regulated cell death triggered by copper overload and the resulting mitochondrial stress. This novel mechanism presents a promising strategy for treating cancer by focusing on the cells' dependence on enhanced metabolic processes. This approach has faced two significant challenges in its clinical translation. The delivery of copper ions to tumor sites is insufficient, and tumors have patient-specific sensitivity to cell death triggered by copper. Sonodynamic therapy (SDT) provides unique benefits, including the ability to penetrate deep tissues and control treatment in both space and time. Nonetheless, its treatment efficacy is frequently reduced by the low-oxygen tumor environment and strong intracellular antioxidant defenses. In this article, we systematically explore the synergistic mechanisms between SDT and cuproptosis. Significantly, we point out that thoughtfully designed nanomedicines function as the key connection to promote this strategic combination. Specifically, ultrasound (US) prompts the controlled release of copper from nanomedicines and simultaneously creates reactive oxygen species (ROS). The ROS reduce intracellular glutathione (GSH) levels, which decreases the cell's defense threshold and makes cancer cells more susceptible to copper-induced cell death. Meanwhile, the copper ions that are released participate in Fenton-like reactions, the core mechanism of chemodynamic therapy (CDT). This leads to the production of more ROS, which in turn increases the oxidative stress caused by SDT. This review offers a critical examination of the therapeutic potential linked to the synergy of SDT-induced cuproptosis. Our focus is on how this synergistic approach not only overcomes multidrug resistance but also triggers strong immunogenic cell death (ICD) when combined with chemotherapy, immunotherapy, and metabolic strategies. In conclusion, we summarize the major challenges in translating to clinical practice, especially regarding large-scale production and biosafety. Looking forward, we suggest developing intelligent nanomedicines that are responsive to the tumor microenvironment, aiming for precise and highly effective cancer therapy.