A Review of Aryl Hydrocarbon Receptor–Mediated Immune Regulation in Cutaneous Squamous Cell Carcinoma Progression

Huiyan Han,1 Qinyi Dong,2 Zijian Zhang,2 Siying Li,1 Han Zhang,1 Xinman Wang,1 Jiahao Bai,1 Lei Shi,1 Xiaoyi Fu,2 Kaili Zheng,1 Lili Liang1 1The Cosmetic and Plastic Surgery Department of Shanxi Provincial People’s Hospital, Shanxi Medical University, Taiyuan, 030012, People’s Republic of China; 2The Third Clinical College, Shanxi University of Chinese Medicine, Taiyuan, People’s Republic of ChinaCorrespondence: Lili Liang, Email [email protected]: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that was initially discovered for its role in mediating the toxicity of environmental pollutants such as dioxins. Recent studies have demonstrated that AhR plays significant roles in various physiological and pathological processes, including immune regulation and tumor development. Cutaneous squamous cell carcinoma (cSCC), the second most common skin malignancy, is closely associated with the immune microenvironment. This review systematically outlines the structure, function, and signaling pathways of AhR, as well as its role in the immune system, with a focus on how AhR influences the progression of cSCC by regulating the functions of various immune cells, including T cells, dendritic cells, macrophages, and myeloid-derived suppressor cells. In particular, this review highlights the central role of the “tryptophan–kynurenine–AhR” axis, along with AhR-mediated regulation of immune checkpoints (such as PD-1/PD-L1, CTLA-4, and TIM-3), its crosstalk with inflammatory signaling pathways (including NF-κB, STAT3, and TGF-β), and the impact of AhR on antigen presentation and immunoediting. Furthermore, it discusses the role of AhR ligands in cSCC and the potential of targeting AhR for therapy, providing a novel theoretical foundation and strategic insights for the immunotherapy of cSCC. This review systematically summarizes the immunomodulatory mechanisms of AhR, integrating findings from studies specific to cSCC and those from other tumor types. It should be noted that some mechanistic evidence is derived from non-cSCC research models, and its applicability to cSCC requires further validation.Keywords: aryl hydrocarbon receptor, cutaneous squamous cell carcinoma, immune system, tumor microenvironment, AhR ligands