Project Summary The tumor suppressor LKB1 is one of the most frequently mutated genes in lung adenocarcinoma (LUAD). This tumor subgroup is resistant to immune checkpoint blockade therapy and is not amenable to molecularly targeted therapies. LUAD with LKB1 mutations is usually smoking-related. Even though females are more susceptible to smoking-related DNA-adduct formation in the lung, the frequency of LKB1-mutant LUAD is significantly lower in females than males in multiple large-scale studies. The underlying mechanism is not known primarily because of the lack of an appropriate model to study this phenomenon. We previously established a genetically engineered mouse model (GEMM) in FVB/N background, which can form KrasG12D/LKB1null (LUAD) in the lung with similar features to human LUAD in tumor characteristics and tumor microenvironment. A meta-analysis of our GEMM model revealed the LUAD formation at 97% in males versus 58% in females. We also established lung cancer cell lines from our GEMM, and the establishment of lung metastases through tail-vein injection in syngeneic animals also encountered a strong sex bias in female hosts. Interestingly, this sex bias can also be observed in immune-compromised mice, such as SCID mice deficient in adaptive immunity. Therefore, we hypothesize that innate immunity in some female hosts can eliminate LKB1-mutant LUAD. Here, we will (i) determine why LKB1-mutant LUAD is susceptible to this innate immunity and (ii) which subpopulation of innate immune cells is responsible for eliminating LKB1-LUAD in some female hosts. The elucidation of this mechanism should provide novel insights into developing new therapeutic strategies for LKB1-mutant LUAD.