A critical review of gold(I) complexes as anticancer agents: from canonical mechanisms to immune activation

Gold(I) complexes are historically used as anti-arthritic drugs, with two FDA-approved examples, auranofin (AF) and sodium aurothiomalate. Gold-based complexes have recently emerged as a class of anticancer agents. Their canonical mechanisms of action are closely tied to coordination chemistry, using various ligands that tune the stability, reactivity, and selectivity toward biomolecular targets. Structure-activity relationship (SAR) studies have validated that phosphines, N-heterocyclic carbenes (NHCs), thiolates, ions (anions), and alkynyl ligands orchestrate the cellular uptake, redox modulation, and interactions with key enzymes, such as thioredoxin reductase (TrxR), and other thiol or selenol enzymes through AuS and/or AuSe bond(s). These chemical and biological features endow gold(I) complexes with polypharmacological properties, including disruption of mitochondrial metabolism, induction of oxidative stress, and activation of apoptotic pathways. Importantly, recent studies have shown that some rationally designed gold(I) complexes, including AF, could interact with the immune system, thereby promoting immunogenic cell death (ICD), altering redox-sensitive cytokine signaling, and reshaping the tumor microenvironment (TME) to potentiate antitumor effects of immunotherapies. These promising preclinical data provide a mechanistic rationale for combining gold(I) complexes with immune checkpoint inhibitors (ICIs) and other immunotherapies, which have shifted cancer treatment to a new paradigm. While significant progress has been made, currently, AF is the only one under clinical trials for cancer. In this review, we intend to outline the principles of drug structure design, mechanistic insights, and medicinal chemistry innovations that have driven the field. We also critically discussed current challenges and proposed future directions for advancing gold(I) complexes. We concluded here that integrating medicinal chemistry-driven design with immuno-oncology strategies really holds great promise for translating more gold(I) complexes into more clinically viable anticancer therapeutics.