The aryl hydrocarbon receptor (AHR) drives human leukocyte antigen (HLA)-II expression in human melanoma.

BACKGROUND: Although HLA-II molecules are classically associated with professional antigen-presenting cells, their expression by cancer cells has been recognized for several decades. It has been linked to immune infiltration, responses to immune checkpoint blockade, and clinical outcomes. However, the regulatory mechanisms governing tumor-associated HLA-II expression remain incompletely understood. METHODS: Genome-wide CRISPR-Cas9 screening was employed to identify candidate regulators of HLA-II expression in human melanoma cells. Key candidates were functionally validated through genetic and pharmacological perturbation approaches. Integrated transcriptomic and epigenomic analyses were conducted to characterize regulatory mechanisms. Retrospective clinical analyses were performed using publicly available The Cancer Genome Atlas (TCGA) datasets to assess associations with immune infiltration, immunotherapy response, and survival. RESULTS: We identified the aryl hydrocarbon receptor (AHR) and its dimerization partner ARNT as critical, FICZ-responsive, positive regulators of HLA-II expression. AHR-ARNT promoted transcription of CIITA through direct binding to its promoter II (pII), in the absence of IFN-γ signaling. Clinically, an AHR-ARNT loss-of-function signature correlated with reduced immune infiltration, poorer response to immunotherapy, and inferior survival across cancer types. CONCLUSIONS: These findings reveal a previously unrecognized regulatory axis controlling HLA-II expression on cancer cells, suggesting that targeting the AHR-ARNT pathway may enhance tumor immunogenicity and improve immunotherapy efficacy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-026-03673-y.