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However, the selective manipulation of copper flux at the subcellular organelle level remains challenging, which hinders the development of mechanism\u2010guided therapeutic interventions for related diseases. We report a modular prochelator platform that integrates organelle\u2010targeting ligands with stimuli\u2010cleavable masking groups to unmask a conserved dithiocarbamate (DTC) chelating motif in situ, enabling precise depletion of exchangeable copper within the targeted subcellular compartment. In triple\u2010negative breast cancer (TNBC) cells exhibiting elevated copper levels, the mitochondria\u2010targeted, reactive oxygen species (ROS)\u2010activatable prochelator DHU\u2010Cuex5 mediates organelle\u2010specific copper sequestration, resulting in selective cytotoxicity that is specifically reversible upon Cu\n                    <jats:sup>2<\/jats:sup>\n                    <jats:sup>+<\/jats:sup>\n                    supplementation. Quantitative mitochondrial profiling reveals that treatment with 1 \u00b5M DHU\u2010Cuex5 for 12\u00a0h reduces cytochrome\u2010c oxidase activity to approximately 40% of control levels, collapses mitochondrial membrane potential (\u0394\u03a8m), and disrupts oxidative phosphorylation, as evidenced by decreased oxygen consumption rate and ATP production. Transcriptomic analysis corroborates these observations, demonstrating downregulation of electron transport chain Complex IV and copper homeostasis\u2010related genes, as well as activation of AMPK signaling and oxidative stress pathways. These systems\u2010level changes are consistent with profound mitochondrial respiratory dysfunction. Intratumoral administration of DHU\u2010Cuex5 inhibits xenograft tumor growth with favorable safety profiles.\n                  <\/jats:p>","DOI":"10.1002\/adhm.71635","type":"journal-article","created":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T05:39:57Z","timestamp":1787377197000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Organelle\u2010Targeted, ROS\u2010Gated Prochelators for Inhibition of Triple\u2010Negative Breast Cancer via Depleting Exchangeable Copper"],"prefix":"10.1002","volume":"15","author":[{"given":"Chengcheng","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery, Minhang Hospital Fudan University  Shanghai P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keyu","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Minhang Hospital Fudan University  Shanghai P. R. 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