Erlotinib-Gold(I) Complex Induces Leukemia Cell DC Differentiation and Remodels the Immunosuppressive Microenvironment

Inducing differentiation of leukemia cells into dendritic cells (DC) is pivotal to reshaping the immunosuppressive microenvironment. Here, we report the synthesis of <b>EG2</b>, an erlotinib-gold(I) complex, which directly prompts the differentiation of acute myeloid leukemia (AML) cells into DCs. A patient-derived xenograft (PDX) model underscores the potent anti-AML activity of <b>EG2</b>. Mechanistic studies reveal that <b>EG2</b> initiates the activation of the PPARγ/RXRα heterodimer by targeting thioredoxin reductase (TrxR) and the epidermal growth factor receptor (EGFR). This activation culminates in the expression of genes associated with the differentiation of the AML cells into DCs as well as pyroptosis, effectively reshaping the immune microenvironment both <i>in vitro and in vivo</i>. Overall, this study marks the first instance of a gold-based small molecule inducing the direct differentiation of tumor cells into immune cells and offers a promising and innovative strategy for the design of AML immunotherapies.