Targeted modulation of dual-metal ion homeostasis to induce ER stress and cuproptosis for synergistic breast tumor suppression

Targeted modulation of metal ion homeostasis in tumor cells has emerged as a promising method for cancer therapy. However, the coordination efficiency and stability of different metal ions posed significant challenges for current multi-metal ions delivery systems. In this study, we presented an innovative strategy that utilized a single-metal ion nanoregulator capable of precisely modulating intracellular dual-metal ions homeostasis. This regulation induced endoplasmic reticulum (ER) stress and cuproptosis, which worked synergistically to inhibit tumor growth. Specifically, a calcium-selective chelator, BAPTA, formed a metal coordination complex with copper ions (Cu 2+ ), which remained stable in the extracellular environment but disassembled upon internalized by tumor cells. Once inside, the released BA selectively chelated cytoplasmic calcium ions (Ca 2+ ), depleting ER Ca 2+ stores and triggering ER stress. This stress activated the PERK/p-eIF2α/ATF4/CHOP apoptotic pathway, leading to tumor cell apoptosis. Meanwhile, Cu 2+ induced cuproptosis and was reduced to Cu + in the cytosol, where it consumed hydrogen peroxide and generated cytotoxic hydroxyl radicals. These radicals induced oxidative stress, which, combined with glutathione depletion, further amplified ER stress and promoted tumor cell apoptosis. Both in vitro and in vivo experiments exhibited that the nanoregulator effectively suppressed tumor growth through apoptosis and cuproptosis pathways, with favorable biocompatibility. This study highlighted the synergistic roles of copper and calcium ions in tumor therapy and introduced a novel strategy for modulating intracellular dual-metal ions homeostasis, offering more efficient and low toxicity anti-cancer treatments.