Accumulating evidence suggests that interferon (IFN) alpha/beta are involved in antitumor immunity and cancer immunoediting, but information on the antitumor effects of IFN alpha/beta in lung cancer is limited. In our study, we elucidated the IFN alpha/beta signature during both human fetal lung development and lung tumorigenesis. Our findings indicated gradual upregulation in the IFN alpha/beta signature during human fetal lung development. In addition, this signature was progressively downregulated in normal human airway epithelial cells from lung cancer patients, in immortalized human bronchial epithelial cell lines from later passages, in late-stage lung squamous cell carcinoma (LSCC) tissues, and in LSCC tissues exhibiting lymph node metastasis. Therefore, from its earliest stages, lung tumorigenesis may be associated with a decreased IFN alpha/beta signature. This association may provide insight to guide the detection of high-risk lung cancer patients.