AHR Activation Drives Cancer Cell-Intrinsic MHC-II expression in Human Melanoma

MHC-II molecules are traditionally restricted to professional antigen-presenting cells (pAPCs), but increasing evidence highlights their expression in cancer cells, where they are associated with enhanced immune infiltration and improved clinical outcomes. However, the mechanisms governing cancer cell-intrinsic MHC-II expression remain poorly understood. Here, through genome-wide CRISPR-Cas9 screening in human melanoma cells, we identify the aryl hydrocarbon receptor (AHR) and its dimerization partner (ARNT) as critical, ligand-responsive regulators of MHC-II expression. Our analyses reveal that AHR–ARNT promotes transcription of the MHC-II transactivator CIITA through direct binding to its promoter II (pII), independently of IFN-γ signaling. Clinically, an AHR–ARNT loss-of-function signature correlates with reduced immune infiltration, poor response to immunotherapy, and inferior survival across cancer types. Together, our findings uncover a previously unrecognized, tumor-intrinsic regulatory axis of MHC-II expression and suggest that targeting the AHR–ARNT pathway may enhance tumor immunogenicity and improve responses to immunotherapy.