Ligand-Engineered Cu(II) Complexes Suppress Stemness and Drug Resistance in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is an aggressive malignancy characterized by cancer stem cell (CSC) enrichment and multidrug resistance. Here, we report a series of Cu(II) complexes ( Cu1–Cu4 ) designed to investigate the impact of ligand engineering on anticancer activity. The lead complexes, Cu3 and Cu4, incorporating an anthracene-appended imidazophenanthroline scaffold, exhibit submicromolar antiproliferative activity against TNBC cell lines, outperforming oxaliplatin under comparable conditions. Mechanistic studies demonstrate that Cu3 and Cu4 induce cell-cycle arrest and apoptosis while suppressing epithelial-mesenchymal transition (EMT) and tumor cell migration. Notably, both complexes significantly attenuate 3D tumor spheroid formation and reduce CSC-associated markers, including the CD44 high /CD24 low subpopulation, indicating a reduction in CSC population and spheroid-forming capacity. Furthermore, Cu3 and Cu4 enhance intracellular retention of doxorubicin by downregulating ABC transporter expression, highlighting their ability to modulate drug-resistance mechanisms. These findings identify ligand-engineered Cu(II) complexes as promising scaffolds for reducing CSC-associated features and overcoming chemoresistance in TNBC.