Photoactivation of the cGAS-STING pathway and pyroptosis by an endoplasmic reticulum-targeting ruthenium(ii) complex for cancer immunotherapy

Abstract

Three multifunctional ruthenium(II) complexes (Ru1–Ru3) modified with cholic acid were synthesized, which exhibited excellent singlet oxygen-generating ability and near-infrared (NIR) aggregation-induced emission (AIE) phosphorescence activity. Cellular toxicity assays revealed that Ru1 displayed pronounced phototoxicity against both human breast cancer cells (MDA-MB-231) and murine breast cancer cells (4T1), achieving a maximum phototoxicity index (PI) of 83.3. Mechanistic studies indicated that Ru1 exhibited superior targeting affinity for the endoplasmic reticulum (ER). Upon irradiation at 450 nm, it stimulated the production of reactive oxygen species (ROS) and initiated ER stress. This stress activated the interferon gene stimulator (STING) pathway's signaling cascade within the ER, prompting a Golgi apparatus response. The consequent activation induced pyroptosis and sequentially engaged the downstream proteins p-TBK1 and p-IRF3 within the STING pathway, thus promoting the secretion of antitumor cytokines and the elicitation of tumor immune responses. In vivo experiments conducted on Balb/c mice have demonstrated significant anti-tumor immune effects exhibited by Ru1. In summary, the immune modulation and targeted intervention by metal complexes represent an innovative and promising therapeutic strategy for cancer. This approach is anticipated to yield new perspectives for the development of metal complexes that augment tumor immunotherapy.