The Aryl Hydrocarbon Receptor: Impact on the Tumor Immune Microenvironment and Modulation as a Potential Therapy

TL;DR

This paper reviews how the aryl hydrocarbon receptor affects cancer progression and the tumor immune environment, and explores its potential as a cancer therapy target.

Contribution

The paper provides a comprehensive review of AhR's dual roles in tumor progression and immune modulation, highlighting gaps in current research and therapeutic potential.

Findings

AhR activation promotes tumor growth through proliferation and epithelial-to-mesenchymal transition.

AhR has both pro- and anti-tumorigenic effects on immune cells in the tumor microenvironment.

Current AhR-targeting therapies show promise in pre-clinical studies but lack clinical success.

Abstract

The aryl hydrocarbon receptor (AhR) is a cytoplasmic and environmental receptor that responds to both exogenous and endogenous ligands to impart a broad range of functions and thereby significantly impact cancer progression. AhR activation impacts both tumor-intrinsic pathways and immune cells in a context-specific manner. Understanding the impact of AhR activation on the tumor immune microenvironment is critical to guide cancer therapies targeting the receptor.

The aryl hydrocarbon receptor (AhR) is a ubiquitous nuclear receptor with a broad range of functions, both in tumor cells and immune cells within the tumor microenvironment (TME). Activation of AhR has been shown to have a carcinogenic effect in a variety of organs, through induction of cellular proliferation and migration, promotion of epithelial-to-mesenchymal transition, and inhibition of apoptosis, among other functions. However, the impact on immune cell function is more complicated, with both pro- and anti-tumorigenic roles identified. Although targeting AhR in cancer has shown significant promise in pre-clinical studies, there has been limited efficacy in phase III clinical trials to date. With the contrasting roles of AhR activation on immune cell polarization, understanding the impact of AhR activation on the tumor immune microenvironment is necessary to guide therapies targeting the AhR. This review article summarizes the state of knowledge of AhR activation on the TME, limitations of current findings, and the potential for modulation of the AhR as a cancer therapy.

Figures