Toward Mitochondrial Targeting of Resistant Triple-Negative Breast Cancer Using Triphenylphosphonium-Conjugated Antimicrobial Peptides.

Metastatic evolution of malignant tumors following standard anticancer therapies and the emergence of resistant cancer cell populations remain major challenges in oncology. One promising strategy is to develop compounds that selectively target mechanisms of therapeutic resistance. Unlike therapy-sensitive malignant cells, which rely primarily on glycolysis for energy, many chemoresistant cells and cancer stem cells (CSCs) preferentially utilize mitochondrial oxidative phosphorylation (OXPHOS). In this study, we employed a triple-negative breast cancer model to demonstrate that short antimicrobial peptides can significantly suppress the metastatic potential of resistant cancer cells and reduce the formation of CSC-like mammospheres by disrupting mitochondrial respiration. This effect was further enhanced by conjugating the peptides to the mitochondrial-targeting cation triphenylphosphonium (TPP). Mechanistic studies revealed that these compounds induce oxidative stress and mitophagy and suppress mitochondrial translation. Collectively, these findings suggest that TPP-conjugated peptides represent a promising therapeutic strategy for targeting OXPHOS-dependent resistance in aggressive solid tumors.