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

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.

This review addresses these gaps in three key ways. First, it provides the first head-to-head comparative analysis of AhR functions across five cancer types: esophageal, gastric, colorectal, hepatocellular, and pancreatic. 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, the authors systematically discuss 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, the paper aims to provide a conceptual basis for biomarker-guided evaluation of AhR-targeted strategies in GI cancers.

The study highlights that while AhR signaling can be harnessed to suppress inflammation and maintain epithelial barriers, its role in promoting immune evasion and metabolic reprogramming complicates therapeutic targeting. The authors caution that the dual nature of AhR function necessitates careful consideration of cellular context before applying targeted interventions. This review serves as a foundational resource for researchers investigating the mechanistic nuances of AhR signaling across diverse gastrointestinal malignancies.

It is important to note that this work represents a synthesis of existing literature rather than new experimental data. The proposed stratification model and therapeutic evaluation framework are conceptual tools intended to guide future research directions. As with all preclinical findings, further validation in clinical settings is required before any targeted therapies can be implemented.