Breaking Chemoresistance in Colorectal Cancer by Targeting Metabolic Plasticity with Palladium Acyclic Diaminocarbene Complexes

The clinical efficacy of first-line oxaliplatin-based treatments in metastatic colorectal cancer (CRC) is universally limited by acquired resistance, a process driven by metabolic plasticity that allows tumors to dynamically reprogram their energy metabolism for survival. To exploit this vulnerability, we developed a novel organometallic scaffold based on palladium(II) complexes bearing acyclic diaminocarbene ligands. The complexes exhibit potent, low-micromolar antiproliferative activity against glycolytic CRC models and, crucially, display undiminished efficacy against oxaliplatin-resistant cells. We establish that their antiproliferative action hinges on the formation of stable H-bonded lipophilic cations under physiological conditions, which selectively target mitochondria of metabolically dysregulated cancer cells. This triggers a critical surge in mitochondrial lipid peroxidation, culminating in a regulated cell death that adapts to the cellular context, manifesting as either apoptosis or non-apoptotic death depending on the metabolic and redox status of the tumor cell.