Beyond Thiol-Enzyme Inhibition: Sterically Bulky NHC-Au(I) Complexes are Catalytically Active Anticancer Agents with Reprogrammed Immunomodulatory Function

Metallodrug-induced immunogenicity offers significant potential for improving the efficacy of cancer immunotherapy with metals such as gold serving as a notable example. However, heavy metals may concurrently disrupt immune cell function, and a few of them can augment immunogenicity without compromising immunological integrity. Here, we report sterically bulky Au(I) complexes as catalytically active anticancer agents with the capability to reprogram immunomodulatory function. Our initial studies identified complex IPr-Au-Cl, characterized by bulky substituents, which catalytically activated an alkyne probe in the presence of GSH and triggered hydride transfer from NADH to NAD⁺. Subsequent structural optimization led to the development of <b>Au-8</b>, which showed an increased catalytic activity and improved cytotoxicity against cancer cells. Although <b>Au-8</b> induced elevated ROS levels and immunogenic CRT exposure in cancer cells akin to auranofin, it triggered unique proteomic responses, notably showing minimal inhibition of thioredoxin reductase 1 (TrxR1), a crucial protein for maintaining immune cell function. Auranofin's inhibition of TrxR1 resulted in immunosuppression at one-seventh of its cytotoxic IC₅₀ against cancer cells. In contrast, <b>Au-8</b> not only maintained but also enhanced immune function <i>in vitro</i>, <i>ex vivo</i>, and <i>in vivo</i>, including activated immunogenic phagocytosis and cytotoxic effects in human peripheral blood mononuclear cells isolated from healthy donors. This study, therefore, presents a novel design for gold compounds that leverages steric hindrance to achieve catalytic anticancer activity without affecting TrxR1, opening avenues for future gold-based therapeutics with desirable immunomodulatory effects.