An Ir(iii)-based type I photosensitizer triggers immunogenic pyroptosis in prostate cancer

Abstract

Pyroptosis, a newly identified potent immunogenic cell death (ICD) form, is attracting growing attention in cancer immunotherapy owing to its capacity to efficiently activate T cell immunity even at a low cell occurrence rate. Precise spatiotemporal control and noninvasive nature endow the photocatalytic system with great potential in immunogenic pyroptosis-based cancer treatment. However, explorations of efficient pyroptosis-inducers for hypoxic tumor microenvironments remain in the early stages. Here, we designed a series of photocatalytic type-I reactive oxygen species (ROS) generators (Ir1–Ir3) to initiate immunogenic pyroptosis in prostate cancer. The fluorescein-decorated Ir(III)-based photosensitizers were designed to take advantage of the triplet-state population via multiple channels and the electron-rich character of the deprotonated fluorescein moiety, thereby modulating type I ROS generation through an effective electron-transfer process. Notably, Ir3, equipped with the electron-donating cyclometalating ligand dtqx (2,3-dithiophen-2-ylquinoxaline), is demonstrated to be the strongest type-I ROS generator and most effective at inducing pyroptosis via the canonical Caspase-1/gasdermin D (GSDMD) pathway. Regarding the subcutaneous and re-challenge prostate cancer-bearing animal models, effective primary tumor inhibition and immunological memory to prevent tumor recurrence and metastasis have been demonstrated. This work highlights a strategy to design Ir(III) complex-based, oxygen-independent photosensitizers as potent pyroptosis-inducing agents for prostate cancer treatment.