The LKB1 Axis in Cancer: Upstream Regulation, Downstream Signaling, and Context-Dependent Functions

Liver kinase B1 (LKB1) is a serine/threonine kinase that serves as a central regulator of cellular energy homeostasis, growth control, polarity, and stress adaptation. Acting as a master kinase, LKB1 activates AMP-activated protein kinase (AMPK) and a family of related kinases, thereby restraining mTORC1 signaling and limiting anabolic, energy-consuming processes. Through these functions, LKB1 has classically been regarded as a tumor suppressor. However, accumulating evidence demonstrates that LKB1 signaling is highly context dependent. While LKB1 loss promotes tumor initiation, immune evasion, and metastatic progression in several epithelial cancers, preserved or contextually co-opted LKB1 signaling can paradoxically support metabolic flexibility, stress tolerance, and survival in select malignancies, including hepatocellular carcinoma and hematologic cancers. This review synthesizes current understanding of the upstream regulatory mechanisms and downstream signaling networks governing LKB1 function, emphasizing its dual and lineage-specific roles in cancer biology and highlighting emerging therapeutic vulnerabilities associated with LKB1 pathway dysregulation.