Aryl hydrocarbon receptor dynamics in esophageal squamous cell carcinoma: From immune modulation to therapeutic opportunities

Table 1 Aryl hydrocarbon receptor signaling and its impact on

Aspect of ESCC	Impact of AhR activation	Mechanism	Ref.
Carcinogenesis
Proliferation	Increased	Upregulates cyclin D1, downregulates p21	[31,33]
Apoptosis	Inhibited	Upregulates anti-apoptotic factors like Bcl-2	[34]
DNA repair	Impaired	Downregulates expression of key DNA repair enzymes	[36]
Metabolic reprogramming	Promotes Warburg effect	Increases reliance on aerobic glycolysis	[28]
Stemness	Enhanced	Promotes self-renewal and differentiation of cancer stem cells	[37,38]
EMT	Induced	Upregulates EMT-inducing transcription factors like Twist1 and Snail	[41,43]
Immune escape
T cell function	Suppressed	Inhibits proliferation and cytokine production of CD8+ CTLs, promotes differentiation of Tregs	[45,46]
Myeloid cell recruitment	Increased	Promotes recruitment and expansion of MDSCs	[47]
Immune checkpoint regulation	Potential upregulation of PD-L1 expression	May contribute to immune escape by inhibiting T cell activity	[49]

AhR: Aryl hydrocarbon receptor; Bcl-2: B-cell lymphoma 2; CD8+ CTLs: CD8+ Cytotoxic T lymphocytes; EMT: Epithelial-mesenchymal transition; ESCC: Esophageal squamous cell carcinoma; MDSCs: Myeloid-derived suppressor cells; PD-L1: Programmed death-ligand 1; Snail: Zinc finger protein SNAI1; Twist1: Twist family BHLH Transcription factor 1; Tregs: Regulatory T cells.

Table 2 Mechanisms of action and potential effects of promising aryl hydrocarbon receptor antagonists on malignancies

AhR ligands	Mechanism of action	Potential effects on malignancies	Ref.
Natural products
Curcumin	Competitive binding to the AhR ligand-binding domain	Suppresses proliferation, migration, and invasion of cancer cells; may enhance anti-tumor immunity	[54,62,63]
Quercetin	Competitive binding to the AhR ligand-binding domain; may also inhibit AhR nuclear translocation	Suppresses proliferation and induces apoptosis in cancer cells	[55]
Resveratrol	May interfere with AhR-DNA binding; may also possess antioxidant and anti-inflammatory properties	May inhibit tumor growth and metastasis	[55,64]
Synthetic ligands
CH-223191	Competitive binding to the AhR ligand-binding domain	Suppresses proliferation and migration of cancer cells	[65]
NH3 (Ammonia)	Competitive binding to the AhR ligand-binding domain	Shows promise in preclinical models, but may have limitations due to potential toxicity	[66]
Small molecule antagonists	Competitive binding to the AhR ligand-binding domain or interfering with AhR dimerization	Several novel small molecules are under development, with preclinical studies ongoing	[67,68]

AhR: Aryl hydrocarbon receptor.