Reimagining AHR in Cancer: From Environmental Sensor to Novel Immunomodulatory Therapeutic Target

The aryl hydrocarbon receptor (AHR) is an environmental sensor in mammals and a ligand-dependent, highly conserved transcription factor. It belongs to the basic helix-loop-helix family of transcription factors and is the only known ligand-activated member within this family. Previous studies have revealed its significant roles in physiological regulation, metabolic homeostasis, and tumorigenesis. AHR governs transcriptional regulation and epigenetic modifications through diverse mechanisms and plays an important role in various types of cancer. In this review, we introduce the history and structure of AHR and summarize its modes of action via canonical and non-canonical pathways. We elaborate on the distinct impact of AHR on mitochondrial metabolism, epigenetics, as well as cell death and fate. Furthermore, we systematically discuss the relationship between AHR and tumor immunity. Finally, we explore the prospects of AHR in the tumor microenvironment, cancer immunity and therapy, and its potential as an immunotherapeutic target, along with current achievements in drug development targeting AHR. These research findings may provide insights into the relationship between AHR and its regulated molecules and pathways in cancer, as well as mechanisms for cancer treatment and intervention.