{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T17:36:34Z","timestamp":1791394594576,"version":"4.3.3"},"reference-count":31,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Wuhan Municipal Health Commission","award":["WX23B39"],"award-info":[{"award-number":["WX23B39"]}],"id":[{"id":"https:\/\/ror.org\/04jjn5s14","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100018536","name":"National Major Science and Technology Project for the Prevention and Control of Emerging, Sudden, and Major Infectious Diseases","doi-asserted-by":"publisher","award":["2025ZD01908702"],"award-info":[{"award-number":["2025ZD01908702"]}],"id":[{"id":"10.13039\/501100018536","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>STK11\/LKB1 mutations are critical drivers of primary resistance to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC); however, the metabolic mechanisms by which STK11 deficiency remodels the tumor microenvironment to induce an immunosuppressive state remain largely elusive. By performing metabolomics and liquid chromatography\u2013mass spectrometry (LC\u2013MS) analysis on tumor interstitial fluid (TIF) from STK11-deficient patient-derived xenograft and syngeneic mouse CMT167 models, we investigated the metabolic landscape and its impact on CD8+ T cell functionality. We further integrated biochemical assays (chromatin immunoprecipitation, co-immunoprecipitation, and dual-luciferase) and engineered small extracellular vesicles to dissect the upstream regulatory network and evaluate therapeutic potential. We identified a significant and specific accumulation of phosphoethanolamine (pEtn) in the STK11-deficient TIF, which directly impairs CD8+ T cell effector functions by downregulating membrane diacylglycerol and blocking proximal T cell receptor signaling. Mechanistically, STK11 loss triggers mitochondrial reactive oxygen species (ROS) accumulation, which inhibits prolyl hydroxylases and prevents the VHL-mediated degradation of HIF1A. Stabilized HIF1A subsequently recruits the demethylase ten-eleven translocation 1 (TET1) to the ETNK2 promoter, driving its epigenetic activation and excessive pEtn synthesis. Clinical analyses confirm that high ETNK2 expression correlates with poor ICI response and shortened survival. Targeted delivery of siETNK2 via EGFR-targeted exosomes effectively lowered TIF pEtn concentrations, restored T cell activity, and sensitized STK11-deficient tumors to PD-1 blockade in vivo. This study elucidates a novel \u2018mitochondrial ROS-HIF1A-TET1-ETNK2\u2019 metabolic\u2013epigenetic axis, providing a precise interventional strategy to overcome genotype-specific immune resistance in NSCLC.<\/jats:p>","DOI":"10.1093\/intimm\/dxag048","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T16:51:41Z","timestamp":1789577501000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>STK11<\/i>\n                    deficiency drives NSCLC immune resistance via ETNK2-mediated phosphoethanolamine accumulation"],"prefix":"10.1093","author":[{"given":"Wei","family":"Zhang","sequence":"first","affiliation":[{"name":"Hubei Branch (Wuhan Pulmonary Hospital) of the National Clinical Research Center for Infectious Diseases, Wuhan Pulmonary Hospital (Wuhan Institute for Tuberculosis Control) , Wuhan ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Hu","sequence":"additional","affiliation":[{"name":"Occupational Disease Prevention and Control Department, Center for Disease Control and Prevention of Yangtze River Navigation Administration , Wuhan, Hubei ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengbin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Tuberculosis Control and Cure, Hubei Branch (Wuhan Pulmonary Hospital) of the National Clinical Research Center for Infectious Diseases, Wuhan Pulmonary Hospital (Wuhan Institute for Tuberculosis Control) , Wuhan 430033 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