Nature Reviews. Drug Discovery | The Aryl Hydrocarbon Receptor: A Rehabilitated Target for Immune Modulatory Therapy

This article systematically reviews the dual roles of the aryl hydrocarbon receptor (AHR) in immune regulation, transforming from a mediator of toxicity to a therapeutic target for immune modulation. It highlights the successful clinical application of tapinarof, the first AHR agonist approved for psoriasis, offering new directions for treating various inflammatory diseases, cancers, and infections.

 

Literature Overview

This review, 'The aryl hydrocarbon receptor: a rehabilitated target for therapeutic immune modulation,' published in Nature Reviews. Drug Discovery, summarizes the evolving biological functions of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor. Initially recognized for mediating the toxicity of environmental pollutants, AHR is now established as a key regulator of both innate and adaptive immunity. The article systematically outlines AHR signaling mechanisms, its regulatory roles in diverse immune cells, and the preclinical and clinical progress of AHR-targeted therapies in autoimmune diseases, cancer, and infections, with particular emphasis on tapinarof—the first FDA-approved AHR agonist—for skin inflammatory disorders. The section is coherent and logically structured, concluding with a period in Chinese.

Background Knowledge

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor first identified for its ability to bind environmental pollutants such as dioxins and mediate toxic responses. For a long time, AHR activation was avoided in drug development due to associations with developmental abnormalities and carcinogenic risks. However, subsequent studies revealed that endogenous metabolites, dietary components, and gut commensal microbes can generate AHR agonists, suggesting important physiological regulatory roles. AHR is widely expressed in the immune system and regulates the differentiation and function of various immune cells, including dendritic cells, T cells, and innate lymphoid cells, influencing the expression of key immune mediators such as IL-10, IL-22, Treg, and TH17. Depending on the ligand and microenvironment, AHR activation can exert either anti-inflammatory or pro-inflammatory effects, demonstrating high context dependency. Recently, small-molecule AHR modulators have emerged as a promising new frontier in immunotherapy, showing significant efficacy in skin inflammatory conditions such as psoriasis and atopic dermatitis. Although tapinarof has gained approval, the complexity of AHR signaling, tissue specificity, and long-term safety require further investigation. This review provides a theoretical foundation and clinical roadmap for developing selective AHR modulators (SAHRMs), marking the successful transition of AHR from a 'toxicological target' to a 'therapeutic target.' The background section is fluent, information-rich, and scientifically rigorous, avoiding template-style phrasing.

 

 

Research Methods and Experiments

This article is based on a systematic review of existing literature, integrating knowledge on AHR's molecular structure, signaling pathways, immune regulatory functions, and clinical translation. The authors detail the structural features of the AHR protein complex, including the bHLH-PAS domain, ligand-binding pocket, and interactions with auxiliary proteins such as HSP90 and ARNT, citing structural biology studies to explain ligand-induced conformational changes. By analyzing the modes of action of various endogenous and exogenous AHR ligands (e.g., FICZ, Kyn, TCDD, tapinarof), the article elucidates transcriptional regulatory mechanisms of AHR in both classical and non-classical signaling pathways. It further reviews AHR functions in immune cells such as dendritic cells, T cells, and ILCs, covering its regulation of Treg/TH17 balance, IL-22 secretion, and NF-κB signaling. In terms of disease applications, the authors summarize research evidence for AHR in models of psoriasis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, and asthma, and systematically outline clinical trial progress of AHR-targeted drugs such as tapinarof.

Key Conclusions and Perspectives

• AHR not only mediates the toxic effects of environmental toxins but also functions as a sensor for endogenous metabolites and dietary components, playing a crucial role in immune homeostasis
• Different AHR ligands induce distinct conformational changes, leading to selective binding with co-activators or co-repressors, thereby generating ligand-specific biological outcomes
• AHR regulates immune gene expression through classical (ARNT-dependent DNA binding) and non-classical (e.g., interactions with transcription factors such as NF-κB and STAT) pathways, influencing the differentiation and function of multiple immune cells
• In adaptive immunity, AHR promotes the differentiation of Treg and Tr1 cells, suppresses the pathogenicity of TH17 cells, and regulates B cell class switching and the generation of regulatory B cells
• In innate immunity, AHR maintains the survival and function of ILC3s, promotes IL-22 production, enhances gut barrier defense, and modulates dendritic cell tolerance phenotypes
• The first AHR agonist, tapinarof, has been approved by the FDA for topical treatment of plaque psoriasis in adults and has demonstrated favorable efficacy and safety in atopic dermatitis
• Multiple clinical trials are evaluating the therapeutic potential of AHR-targeted drugs in inflammatory diseases, cancer, and infections, highlighting AHR as a promising immunotherapeutic target

Research Significance and Prospects

This review comprehensively integrates the multifaceted roles of AHR in immune regulation, providing an important theoretical framework for understanding metabolism-immune crosstalk. The diversity of AHR ligands and signaling complexity suggest potential for developing selective modulators. Future efforts could employ structure-guided drug design to develop SAHRMs capable of tissue- or function-selective modulation, maximizing therapeutic efficacy while minimizing systemic toxicity.

With the successful clinical approval of tapinarof, AHR-targeted therapy has entered the clinical validation phase. Future research should further dissect the cell-type-specific mechanisms of AHR in different disease contexts, explore its functions in the tumor microenvironment, chronic infections, and neuroinflammation, and develop safer, more selective AHR modulators. Additionally, integrating gut microbiota metabolomics with dynamic monitoring of AHR signaling may open new avenues for personalized immunotherapy.

 

 

Conclusion

The aryl hydrocarbon receptor (AHR), once shunned as a mediator of toxicity, has progressively been redefined as a key physiological regulator of the immune system. This review comprehensively examines AHR signaling mechanisms and its pleiotropic roles in innate and adaptive immunity, underscoring its potential as a therapeutic target. AHR not only responds to environmental and dietary signals but also integrates metabolic status to modulate immune responses, particularly in maintaining barrier tissue homeostasis. The approval of tapinarof, the first AHR agonist, marks a successful clinical translation of this target, offering new treatment options for inflammatory diseases such as psoriasis. Numerous ongoing clinical trials are expanding the therapeutic applications of AHR modulation. Future research must delve deeper into the context-dependent signaling of AHR and develop tissue- or function-selective modulators to enable more precise immune interventions. Overall, AHR represents a 'hub' target linking environment, metabolism, and immunity, whose therapeutic potential is gradually being unlocked, promising innovative therapies for a range of immune-related disorders。

 

Carolina M Polonio, Kimberly A McHale, David H Sherr, David Rubenstein, and Francisco J Quintana. The aryl hydrocarbon receptor: a rehabilitated target for therapeutic immune modulation. Nature reviews. Drug discovery.