Erlotinib-Gold(I)\nComplex Induces Leukemia Cell DC\nDifferentiation and Remodels the Immunosuppressive Microenvironment

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