Targeting metalloptosis in tumor therapy: from molecular mechanisms to application of metal nanoparticles

Metal ions-based regulated cell death (RCD), a form of cell death involving metal ions and controlled by one or more cascade signaling pathways, has recently been termed “metalloptosis”. Given the rapid advances in understanding metalloptosis in malignant progression and nanotherapeutics, this review elucidates the latest progress in metalloptosis, focusing on the roles of various metal ions and the targeting of metalloptosis in cancer therapy and nanomedicine. We briefly describe the essential discoveries of RCD and comprehensively summarize the current major regulatory signaling pathways of emerging metalloptosis forms, including ferroptosis, cuproptosis, lysozincrosis, manganism, calcicoptosis, and necrosis by sodium overload (NECSO). Additionally, we demonstrated the effects of metalloptosis on malignant neoplastic progression and the tumor microenvironment (TME). Furthermore, we discuss the feasibility of targeting metalloptosis pathways using metal nanoparticles (MNPs) for cancer therapy and overcoming drug resistance in cancer cells. We hope that this review will provide both fundamental insights and translational outlooks for harnessing metalloptosis in precision oncology.