Triphenylphosphonium-based mitochondrial targeting in cancer therapy: mechanisms, progress, and perspectives
Min Yang, Jiaming Ou, Haibo Yan, Yun He, Linling Gan, Shao-Lin Zhang
Abstract
Targeting mitochondria has emerged as a promising anticancer strategy, as these organelles regulate tumor metabolism, apoptosis, and drug resistance. Triphenylphosphonium (TPP)-based strategies leverage the mitochondrial membrane potential to achieve selective accumulation in cancer cells, thereby providing a versatile platform for advancing precision cancer therapy. This review summarizes recent progress in the development of TPP-based anticancer agents, their mechanisms of action, and the current challenges. We also highlight future research directions, which will focus on designing multifunctional TPP molecules, integrating TPP-based therapeutics with complementary treatment modalities, and developing tissue- or cell-specific smart delivery systems. Additional promising strategies include combining TPP-based therapies with immunotherapy to overcome tumor immune evasion, targeting mitochondrial DNA to disrupt cancer bioenergetics, and employing TPP conjugates for fluorescence imaging to monitor drug distribution and mitochondrial targeting efficiency. Collectively, these approaches are expected to accelerate the clinical translation of TPP-mediated mitochondrial therapies, opening new avenues for precision oncology.