An Ir(III)-based Type I Photosensitizer Triggers Immunogenic Pyroptosis in Prostate Cancer

Abstract

Pyroptosis, a newly characterized potent immunogenic cell death (ICD) modality, is gathering increasing attention in cancer immunotherapy for the ability to activate T cell immunity efficiently even at low incidence. The precise spatiotemporal control and noninvasive nature endow photocatalytic system with great potential in immunogenic pyroptosis-based cancer treatment. However, the exploration of efficient pyroptosis inducers for hypoxic tumor microenvironment remains in its early stages. Here, we designed a series of photocatalytic type-I reactive oxygen species (ROS) generator (Ir1–Ir3) to initiate immunogenic pyroptosis in prostate cancer. The fluorescein decorated Ir(III)-based photosensitizers were designed to take advantage of the triple state population via muti-channels and the electron-rich character of deprotonated fluorescein moiety, thereby modulating type I ROS generation through an effective electron transfer process. Noteworthy, Ir3, equipped with the electron donating cyclometalating ligands dtqx (2,3-dithiophen-2-ylquinoxaline), is demonstrated to be the strongest type-I ROS generator and superior for inducing pyroptosis via canonical Caspase-1/gasdermin D (GSDMD) pathway. Regarding the subcutaneous and remote re-challenge prostate cancer-bearing animal models, an effective primary tumor inhibition and immunological memory to prevent tumor recurrence and metastasis have been achieved. This work highlights a strategy to design Ir(III) complex-based, oxygen-independent photosensitizers as potent pyroptosis-inducing agents in prostate cancer treatment.