Recent advances in metal ions overloading for tumors: Mechanisms, nanomaterials, and therapies

Metal ions serve as indispensable regulators in fundamental biological processes, maintaining critical physiological functions including osmotic equilibrium, acid-base regulation, intracellular signaling, and biomolecular recognition. Perturbations of ionic homeostasis can disrupt cellular integrity, leading to functional impairment and ultimately programmed cell death. Capitalizing on this paradigm, emerging nanotherapeutic approaches have pioneered the strategic induction of tumor-selective ions overloading as a potent anticancer strategy. This comprehensive review critically evaluates the roles of key metal ions (Na + , K + , Ca 2+ , Cu 2+ , Zn 2+ , Fe 2+/3+ , Mn 2+ ) in tumor progression and their mechanisms of action when overaccumulated, and highlights innovative nanomaterial designs that exploit ions overloading to induce apoptosis, pyroptosis, or immunogenic cell death. Meanwhile, the combinatorial approaches integrating ions-overloading with other therapy including immunotherapy, chemodynamic therapy, et al. would be discussed. By integrating the mechanisms and contemporary research advances, this work provides a conceptual framework for developing next-generation of ions-disrupting nanomedicines and identifies promising directions for combinatorial anticancer regimens. (1) Critically evaluates the roles of key metal ions (Na + , K + , Ca 2+ , Cu 2+ , Zn 2+ , Fe 2+ / 3+ , Mn 2+ ) in tumor progression and their mechanisms of action when overaccumulated;(2) Highlights innovative nanomaterial designs that exploit ion interference to induce apoptosis, pyroptosis, or immunogenic cell death;(3) Discusses the combinatorial approaches integrating ions-overloading with other therapy including immunotherapy, chemodynamic therapy, et al.;(4) Outlines the unresolved challenges in targeting specificity, toxicity mitigation, and clinical translation.