Cyclometalated iridium complex as a PD-L1 inhibitor: Suppressing expression via COX-2 blockade

Metal-based Programmed Cell Death Ligand 1 (PD-L1) inhibitors partially overcome the limitations of small-molecule inhibitors, such as ambiguous targeting and complex synthetic processes. This study explores a cyclometalated iridium(III) complex Ir-FA by incorporating bioactive natural product trans-ferulic acid (FA), which could be a promising metal-based PD-L1 inhibitor. Ir-FA demonstrated selective cytotoxicity against A549 cells while exhibiting no toxicity toward normal HLF cell line. Mechanistic studies revealed that Ir-FA induces mitochondrial dysfunction via reactive oxygen species (ROS) overproduction and membrane potential collapse. Concurrently, Ir-FA effectively suppressed the expression and activity of key inflammatory mediators, cyclooxygenase-2 (COX-2) and its downstream product prostaglandin E2 (PGE2). Crucially, this combined action, mitochondrial impairment and COX-2/PGE2 inhibition, resulted in the marked downregulation of intracellular PD-L1 expression, which might help suppress the tumor immune evasion. These findings highlight the potential of exploiting the synergistic effects of iridium coordination chemistry and anti-inflammatory activity to develop innovative metal-based agents targeting the Programmed Cell Death Protein 1/PD-L1 immune checkpoint pathway. This work created a transformative platform for developing multifunctional metallodrugs with synergizing chemotherapy and immune activation, holding significant value for cancer treatment.