Liver X receptors (LXRαβ) play essential roles in the maintenance of the normal functions of macrophages, in modulation of immune system responses and cholesterol homeostasis. We have reported that LXRαβ-/-mice develop squamous cell lung cancer. We now report that those LXRαβ-/-mice, which live to 18-months of age, spontaneously develop a second type of lung cancer resembling a rare subtype of NSCLC (TTF-1 and P63-positive). The lesions are characterized as follows: a high proliferation rate; a marked accumulation of abnormal macrophages; an increase in the number of regulatory T cells; a remarkably low level of CD8+cytotoxic T lymphocytes; enhanced TGFβ signaling; an increased expression of matrix metalloproteinases accompanied by degradation of lung collagen; and a loss of estrogen receptor β (ERβ).Because NSCLC is associated with cigarette smoking, we investigated the possible links between loss of LXRαβ and CS. A Kaplan-Meier Plotter database revealed reduced expression of LXRαβ and ERβ was correlated with low overall survival (OS). Thus, reduction of LXRαβ expression by cigarette smoking may be one mechanism through which CS causes lung cancer. The possibility that maintenance of LXRαβ and ERβ signaling could be used in the treatment of NSCLC needs further investigation.