STK11 deficiency drives NSCLC immune resistance via ETNK2-mediated phosphoethanolamine accumulation

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ID: 328743
2026
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Abstract
Abstract 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 (TME) to induce an immunosuppressive state remain largely elusive. By performing metabolomics and liquid chromatography-mass spectrometry (LC-MS) analysis on tumor interstitial fluid (TIF) from STK11-deficient patient-derived xenograft (PDX) and syngeneic mouse CMT167 models, we investigated the metabolic landscape and its impact on CD8+ T cell functionality. We further integrated biochemical assays (ChIP, Co-IP, and dual-luciferase) and engineered small extracellular vesicles (sEVs) 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 (DAG) and blocking proximal T cell receptor (TCR) signaling. Mechanistically, STK11 loss triggers mitochondrial reactive oxygen species (ROS) accumulation, which inhibits prolyl hydroxylases (PHDs) and prevents the VHL-mediated degradation of HIF1A. Stabilized HIF1A subsequently recruits the demethylase 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 "mitochondrial ROS-HIF1A-TET1-ETNK2" metabolic-epigenetic axis, providing a precise interventional strategy to overcome genotype-specific immune resistance in NSCLC.
Reference Key
openalex_W7213419649 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Wei Zhang, Jing Hu, Zhengbin Zhang
Journal international immunology
Year 2026
DOI
10.1093/intimm/dxag048
URL
https://doi.org/10.1093/intimm/dxag048
Keywords Keywords not found

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