A Molecular-Targeting Photosensitizer to Inhibit DNA Damage Repair System and Induce cGAS-STING Pathway Activation for Photo-Immunotherapy of Ovarian Cancer

Abstract

Poly(ADP-ribose) polymerase (PARP) inhibitors are commonly utilized in the clinical management of patients with platinum-sensitive recurrent and late-stage ovarian cancer, which constitutes a significant proportion of gynecological cancer-related mortality. Nonetheless, the constraints of their monofunctional properties and limited therapeutic efficacy observed in advanced cancer cases necessitate the exploration of more potent therapeutic strategies for the management of ovarian cancer. The present study describes the development of QTABI, a PARP-targeting photosensitizer capable of producing reactive oxygen species with light irradiation. Simultaneously, it exhibits significant inhibition of PARP activity, induction of deoxyribonucleic acid (DNA) damage, and consequent synthetic lethality. Furthermore, QTABI can effectively promote the accumulation of cytosolic DNA and activate the cyclicGMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway under light irradiation, thereby eliciting potent anti-tumor immune responses and ultimately boosting anti-cancer efficacy. Collectively, these findings suggest that QTABI is a multi-functional photosensitizer, which targets the DNA-damaging repair system and activates the cGAS-STING pathway, offering a promising combination photo-immunotherapy strategy for treating ovarian cancer.