This study explores the use of π-expansive ligands to enhance the excited state lifetimes of Ir(III) half-sandwich complexes, aiming to improve their photodynamic therapy (PDT) efficiency. The researchers synthesized and characterized a series of Ir(III) complexes with different π-expansion degrees in their C′N ligands, including [Cp*Ir(C′N)L]BF4 and [Cp*Ir(C′N)Cl] formulas. Complexes with more π-expansive ligands exhibited significantly higher phototoxic indexes (PI) and were effective photosensitizers, with PI values exceeding 2000. Time-dependent density functional theory (TD-DFT) calculations explained the enhanced π-expansion effect. These complexes produced reactive oxygen species (ROS) at the cellular level, leading to mitochondrial membrane depolarization, DNA cleavage, NADH oxidation, and lysosomal damage, ultimately activating apoptosis and secondary necrosis. The study highlights the potential of these half-sandwich iridium cyclometalated complexes as active PDT agents, offering a promising approach to reduce side effects in cancer treatment.This study explores the use of π-expansive ligands to enhance the excited state lifetimes of Ir(III) half-sandwich complexes, aiming to improve their photodynamic therapy (PDT) efficiency. The researchers synthesized and characterized a series of Ir(III) complexes with different π-expansion degrees in their C′N ligands, including [Cp*Ir(C′N)L]BF4 and [Cp*Ir(C′N)Cl] formulas. Complexes with more π-expansive ligands exhibited significantly higher phototoxic indexes (PI) and were effective photosensitizers, with PI values exceeding 2000. Time-dependent density functional theory (TD-DFT) calculations explained the enhanced π-expansion effect. These complexes produced reactive oxygen species (ROS) at the cellular level, leading to mitochondrial membrane depolarization, DNA cleavage, NADH oxidation, and lysosomal damage, ultimately activating apoptosis and secondary necrosis. The study highlights the potential of these half-sandwich iridium cyclometalated complexes as active PDT agents, offering a promising approach to reduce side effects in cancer treatment.