Importantly, using SEPIRA, we are here able to shed new light on the potential role of the AHR/AHRR pathway in lung cancer etiology, linking its inactivation to an altered immune response in the lung epithelium, while also identifying other regulatory pathways (e.g. FOXJ1/HIF3A) which become inactivated in smoking-associated lung cancer, in precursor lung cancer lesions, and in normal cells exposed to smoke carcinogens. Here, FOXJ1 is linked to lung cancer.