{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:15:02Z","timestamp":1788430502682,"version":"build-2803163510"},"reference-count":110,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Peutz\u2013Jeghers syndrome (PJS) presents an apparent biological paradox: heterozygous germline pathogenic variants in STK11 predispose to predominantly benign hamartomatous growth while conferring a markedly elevated lifetime risk of cancer, whereas somatic STK11 inactivation in established tumors is frequently associated with aggressive progression and therapeutic resistance. STK11 encodes liver kinase B1 (LKB1), a serine\/threonine kinase that integrates metabolic, oxidative, architectural, and immune stress responses. Rather than acting solely as a direct brake on proliferation, LKB1 couples cellular growth, survival, and tissue organization to environmental fitness. We therefore propose a context-dependent stress adaptation framework in which impairment of STK11\/LKB1 signaling relaxes stress-imposed constraints on cellular fitness, while the ultimate biological outcome is determined by allelic status, tissue context, and cooperating genetic alterations. In PJS, a heterozygous germline STK11 pathogenic variant creates a constitutional cancer predisposed state in which one functional allele is initially retained, although subsequent loss or impairment of the remaining allele may occur during tumor evolution. In sporadic cancers, somatic STK11 inactivation is often biallelic and frequently cooperates with alterations in KRAS, KEAP1, TP53, NF1, or PI3K-pathway genes. These genetic contexts can promote metabolic reprogramming, redox adaptation, autophagy dependence, immune exclusion, cellular plasticity, and therapeutic resistance, with the strongest mechanistic and clinical evidence currently derived from lung adenocarcinoma (LUAD). Within this framework, enhanced persistence under metabolic, oxidative, immune, and therapy-induced stress does not exclude proliferative effects of STK11 loss but provides a permissive background upon which cooperating oncogenic programs can drive clonal expansion and malignant progression. Stress adaptation creates dependencies on interconnected buffering systems, including antioxidant defenses, autophagy, metabolic plasticity, and ferroptosis suppression. Therapeutic strategies that simultaneously disrupt multiple compensatory pathways may therefore exceed tumor adaptive capacity, convert stress tolerance into therapeutic vulnerability, and provide a rational framework for treating LKB1-deficient tumors and other stress-adapted cancers.<\/jats:p>","DOI":"10.3390\/cancers18172845","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T09:20:43Z","timestamp":1788427243000},"page":"2845","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["STK11\/LKB1 Loss in Cancer: From Developmental Constraint to Stress-Adapted Malignancy"],"prefix":"10.3390","volume":"18","author":[{"given":"Yu","family":"Kang","sequence":"first","affiliation":[{"name":"Lab of Hereditary Gynecologic Oncology, School of Medicine, Westlake University, Hangzhou 310024, China"},{"name":"Department of Obstetric and Gynecology, Affiliated Hangzhou 1st People\u2019s Hospital, School of Medicine, Westlake University, Hangzhou 310006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3115-0007","authenticated-orcid":false,"given":"Yanhong","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9262-7473","authenticated-orcid":false,"given":"Xiao-Yan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Lab of Female Reproductive Endocrine Related Disease, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-Ou","family":"Liu","sequence":"additional","affiliation":[{"name":"Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Lab of Female Reproductive Endocrine Related Disease, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong-Jian","family":"Xu","sequence":"additional","affiliation":[{"name":"Lab of Hereditary Gynecologic Oncology, School of Medicine, Westlake University, Hangzhou 310024, China"},{"name":"Department of Obstetric and Gynecology, Affiliated Hangzhou 1st People\u2019s Hospital, School of Medicine, Westlake University, Hangzhou 310006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4747-4951","authenticated-orcid":false,"given":"Yanying","family":"Huo","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Rutgers Cancer Institute, 195 Little Albany Street, New Brunswick, NJ 08903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"22","DOI":"10.4103\/jcrt.JCRT_862_16","article-title":"Oxidative stress and its role in cancer","volume":"17","author":"Jelic","year":"2021","journal-title":"J. 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