Context-dependent functions of the aryl hydrocarbon receptor in gastrointestinal cancers: from microenvironmental regulation to precision targeted therapy

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor with context-dependent roles in gastrointestinal (GI) tumor development. Depending on cellular context and microenvironment, AhR can preserve epithelial integrity, suppress inflammation, and inhibit tumor growth, but it can also promote immune evasion and metabolic reprogramming to drive tumor progression. Most existing reviews have focused on a single GI tumor type or functional dimension, and the concept of AhR as a context-dependent signaling hub has not been effectively linked to therapeutic stratification across the full spectrum of GI malignancies. No prior review has systematically compared AhR across five GI cancer types—esophageal, gastric, colorectal, hepatocellular, and pancreatic—or addressed the translational gap between preclinical data and clinical application. This review addresses these gaps in three key ways. First, it provides the first head-to-head comparative analysis of AhR functions across these five cancer types. Second, it adopts a functional stratification framework integrating five core mechanistic dimensions—tumor stemness, epithelial-mesenchymal transition, immune remodeling, metabolic reprogramming, and drug resistance—and proposes a three-dimensional AhR stratification model. Third, it systematically discusses emerging AhR-targeted therapeutic strategies—including antagonists, selective AhR modulators (SAhRMs), PROTACs, combination therapies, and microbiome-based interventions—while critically evaluating translational challenges. By establishing this context-informed framework, we aim to provide a conceptual basis for biomarker-guided evaluation of AhR-targeted strategies in GI cancers.