{"doi":"10.1093/jnci/djaf138","title":"Suppression of LKB1-mutant lung adenocarcinoma by natural killer cells from females","abstract":"BACKGROUND: This study addressed the enigma of sex differences in smoking-related lung cancer, particularly focusing on the low LKB1 mutation frequency in female patients with lung adenocarcinoma. METHODS: Sex bias was studied with a genetically engineered mouse model and various tail-vein injection models. Immune cells were analyzed by antibody-depletion study, flow cytometry, and immunofluorescence. The relevance of our findings to human disease was validated by evaluating various lung adenocarcinoma datasets. All statistical tests are 2-sided. RESULTS: A statistically significant percentage of females are resistant to LKB1-mutant tumor formation in our models, reflecting this sex difference in humans. Natural killer (NK) cells were identified as a critical factor in this sex-biased response. This sex difference was observed primarily in LKB1-mutant lung adenocarcinoma, probably due to their low major histocompatibility complex class I level, making them the ideal target for NK cells through the missing-self recognition. Although females resistant to LKB1-mutant lung adenocarcinoma formation did not have enhancement of any specific NK subpopulation, our immunofluorescence analysis revealed high numbers of NKs in female lungs even with the presence of LKB1-mutant lung adenocarcinoma. Our gene set enrichment analysis of The Cancer Genome Atlas-lung adenocarcinoma dataset also showed that female LKB1-mutant lung adenocarcinoma patients have a stronger NK-mediated response after adjusting for other male-female differences using the LKB1 wild-type lung adenocarcinoma dataset. CONCLUSION: Females have a stronger NK-mediated response against LKB1-mutant lung adenocarcinoma, which was present in our mouse model and the human lung adenocarcinoma dataset. This study revealed a novel role of NK cells in suppressing LKB1-mutant lung adenocarcinoma in females, which should be assessed in the clinical setting in the future.","journal":"JNCI Journal of the National Cancer Institute","year":2025,"id":568463,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9618,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1472713,"name":"Rui Jin","orcid":"0000-0003-3946-1181","position":1,"is_corresponding":false},{"id":306718,"name":"Lenore Monterroza","orcid":null,"position":2,"is_corresponding":false},{"id":368336,"name":"Xiuju Liu","orcid":"0000-0002-3354-6478","position":3,"is_corresponding":false},{"id":370050,"name":"Chunzi Huang","orcid":null,"position":4,"is_corresponding":false},{"id":1253424,"name":"Angelo Marra","orcid":"0009-0004-0004-4027","position":5,"is_corresponding":false},{"id":271941,"name":"Xiulei Mo","orcid":"0000-0002-7558-3453","position":6,"is_corresponding":false},{"id":254877,"name":"Haian Fu","orcid":"0000-0002-2362-7979","position":7,"is_corresponding":false},{"id":254874,"name":"Melissa Gilbert‐Ross","orcid":"0000-0002-1960-8302","position":8,"is_corresponding":false},{"id":275301,"name":"Adam I. Marcus","orcid":"0000-0003-0484-3569","position":9,"is_corresponding":false},{"id":393272,"name":"Rabindra Tirouvanziam","orcid":"0000-0003-3526-9985","position":10,"is_corresponding":false},{"id":253866,"name":"Yuan Liu","orcid":"0000-0001-8926-3058","position":11,"is_corresponding":false},{"id":867412,"name":"Frank Schneider","orcid":"0000-0003-2332-3278","position":12,"is_corresponding":false},{"id":275298,"name":"Wei Zhou","orcid":"0000-0002-6783-9957","position":13,"is_corresponding":false},{"id":370049,"name":"Yijian Fan","orcid":null,"position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T02:56:52.212268Z","pmid":"40511603","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}