Mitochondria-targeted iridium(III)-PF-06840003 conjugates: Apoptosis induction, IDO inhibition and ICD response

Indoleamine 2,3-dioxygenase (IDO) is a potential target for tumor immunotherapy. The growing evidence suggests that IDO inhibitors can exert synergistic effects with chemotherapy drugs. In this study, six complexes, comprising three iridium(III) complexes Ir-PF-1-3 and three ruthenium(II) complexes Ru-PF-1-3, were synthesized through the coupling of an IDO inhibitor PF-06840003 (PF) with Ir(III) and Ru(II) complexes. Among them, iridium(III) complexes Ir-PF-1-3 exhibited excellent cytotoxicity against various cancer cells, especially HeLa human cervical cancer cells. Ir-PF-1-3 exhibited potent anti-metastatic properties, as evidenced by their ability to inhibit the migration and colony formation of HeLa cells. Furthermore, Ir-PF-1-3 could be hydrolyzed in the cellular environment and released the IDO inhibitory active component PF-06840003, exerting an IDO inhibitory effect. Meanwhile, Ir-PF-1-3 mainly located in mitochondria, where they disrupt mitochondrial structure and function. This is manifested by a decrease in mitochondrial membrane potential (MMP) and an increase in reactive oxygen species (ROS) levels. During apoptosis and immunogenic cell death (ICD) induction, there is also G2/M phase cycle arrest.