Cuproptosis-based nanomedicine in cancer metastasis synergistic therapy

Cancer metastasis is a critical indicator of cancer progression and serves as a major cause of cancer-related deaths. Cuproptosis is a novel form of regulated cell death proposed in 2022. Unlike ferroptosis and other known regulated cell deaths (RCDs), cuproptosis has a unique regulatory pathway, and its major biochemical features include copper overload, lipoylated tricarboxylic acid cycle protein aggregation, and the loss of iron-sulfur cluster protein. Cuproptosis-based nanomedicine provides novel therapeutic insights for metastatic cancer treatment. The close link between cuproptosis and cancer therapy has been explored, and several therapeutic strategies have been developed, including copper ionophores and drug delivery systems. Cuproptosis-based nanotherapeutic strategies may enable controlled and selective drug release, and through the multifaceted actions of copper metallocompounds, achieve multimodal theranostic modalities or organically synergize with other regulated RCD pathways. This integration enhances antitumor effects and biosafety, overcomes tumor resistance, and improves the tumor microenvironment. In this review, we systematically delineate the mechanisms of cuproptosis and its current therapeutic implications in metastatic malignancies. We further critically analyze these synergistic therapeutic approaches, prospect emerging applications of cuproptosis-based nanomedicine in metastatic oncology, and highlight their untapped therapeutic potential. Ultimately, we anticipate this exploration will inform innovative clinical management strategies for cancer patients with metastasis.