Amplification of cGAS-STING pathway with "single-molecule multitarget" nanoparticles for chemo-immunotherapy of ovarian cancer

Abstract

With a low autoimmune risk and dedicated induction of type Ⅰ interferon production in immunotherapy, "STING therapy" holds broad prospects in the treatment of aggressive and metastatic cancers such as ovarian cancer (OC). Inducing pyroptosis constitutes a promising approach for activating the anti-tumor immune response. Nevertheless, compared to combination therapies, "single-molecule multitarget" drugs possess the merits of a lower interaction risk, more predictable pharmacokinetics and a lower cost of clinical trials. Therefore, the present study was conducted to construct a structurally stable nanoparticles (TPAQu-Pt@HA NPs) with controlled drug release behavior and active targeting ability based on a self-designed and synthesized photo-platinum compound (TPAQu-Pt) with aggregation-induced emission (AIE) effect without excipients. The NPs attained "single-molecule multitarget" effect via three mechanisms: 1) causing nuclear and mitochondrial DNA damage and cytoplasmic leakage of double-stranded DNA (dsDNA), effectively activating cGAS-STING pathway; 2) inducing pyroptosis benefited from the AIE effect conferring a stronger ROS-generating capacity; 3) photothermal therapy worsened mitochondrial dysfunction and intensified pyroptosis, amplifying activation of cGAS-STING pathway and the subsequent anti-tumor immune response. In conclusion, this study provided a scientific basis for the molecular modification of cisplatin, which was expected to improve the treatment status of OC.

Keywords: Chemo-immunotherapy; Cisplatin; Ovarian cancer; Pyroptosis; Single-molecule multitarget; cGAS-STING pathway.