IR-2

Exploring photosensitizers that efficiently generate oxygen-independent hydroxyl radical (•OH) and activate highly immunogenic PANoptosis and ferroptosis shows promise in addressing the limited efficacy of photodynamic immunotherapy (PDI) in the hypoxic and immunosuppressive tumor microenvironment (TME). However, challenges still exist due to the unsatisfactory •OH production efficiency in most organic photosensitizers and the unresolved relationship between •OH and PANoptosis. Here, we designed and synthesized two novel iridium(III) complexes, Ir1 and Ir2. Notably, Ir1 produced more type I/II reactive oxygen species under light versus Ir2 and the clinically-used Chlorin e6 (Ce6), including a 25-fold higher •OH yield than both controls. Under extreme intracellular hypoxia, where superoxide anion (O₂^•-) and singlet oxygen (¹O₂) were restricted, Ir1 maintained normoxia-equivalent •OH production, which endowed it with remarkable phototoxicity (IC₅₀ = 0.98 μM) and effective phototoxic index (PI = 3.05). Mechanistically, the •OH produced by Ir1 induced PANoptosis by increasing the expression of cleaved Caspase-3, GSDMD-N, and p-MLKL, and activated ferroptosis through the GSH-GPX4-LPO axis. Subsequently, Ir1 induced immunogenic cell death by enhancing the release of damage-associated molecular patterns under hypoxia, leading to a 1.8-fold increase in dendritic cell maturation. In melanoma-bearing mice, Ir1 achieved 89% reduction in tumor volume and transformed the immunosuppressed "cold" tumors to the inflamed "hot" phenotypes. This work establishes that the efficient •OH generation from iridium(III)-based photosensitizer can synergistically trigger PANoptosis and ferroptosis. This constitutes a viable approach for achieving effective PDI in hypoxic and immunosuppressive TME.