{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSTK11, which encodes the serine/threonine kinase LKB1, functions as a master metabolic sensor by directly phosphorylating AMP‐activated protein kinase (AMPK) and a family of AMPK‐related kinases. Activation of LKB1 by binding partner proteins such as STRAD (via a pseudokinase mechanism) and MO25, as well as its regulation by post‐translational events including acetylation/deacetylation, enables it to couple changes in cellular AMP/ATP ratios to downstream pathways that regulate mTOR and protein translation. In vitro and genetic studies demonstrate that LKB1 directly phosphorylates the activation‐loop residue (Thr172) on AMPK and activates multiple kinases involved in cellular homeostasis and polarity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its biochemical roles, STK11/LKB1 is a critical tumor suppressor. Germline loss‐of‐function mutations cause Peutz–Jeghers syndrome, while somatic inactivation is common in sporadic cancers—including lung, cervical, and pancreatic carcinomas—where LKB1 loss cooperates with oncogenes (for example, mutant KRAS) to accelerate tumor initiation, promote histological heterogeneity and metastasis, and impair programmed cell death. These genetic studies establish LKB1 as a key barrier to malignant transformation and underscore its importance for genomic stability and cell‐cycle control."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBy regulating key metabolic checkpoints, LKB1 also orchestrates cellular responses to nutrient stress, reprogramming metabolic fluxes and controlling autophagy. Activation of the LKB1–AMPK axis under conditions of glucose deprivation or metabolic insult not only adjusts biosynthetic pathways and energy production but also influences epigenetic modifications that facilitate tumor growth. In various models, LKB1‐dependent signaling has been shown to modulate autophagic flux and the cell’s response to metabolic stress—sometimes via regulation by microRNAs or by crosstalk with adipocytokine and growth factor signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "24", "end_ref": "33"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAlterations in STK11/LKB1 further have profound effects on the tumor immune microenvironment. Loss of LKB1 expression is associated with reduced PD‐L1 expression, diminished infiltration of cytotoxic lymphocytes, and resistance to immune checkpoint blockade therapy. Such immune evasion mechanisms help explain the aggressive clinical behavior and low response rates to PD‐1–targeted antibodies observed in cancers, particularly in KRAS–mutant lung adenocarcinoma."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "34", "end_ref": "38"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "A F Baas, J Boudeau, G P Sapkota, et al. 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