Molecular insights and therapeutic implications for the tumor suppressor role of LKB1 in non-small cell lung cancer.

As a master serine/threonine kinase, LKB1 phosphorylates a network of downstream kinases that regulate energy homeostasis, polarity, and cellular stress adaptation. As such, LKB1 functions as a pivotal tumor suppressor in non-small cell lung cancer (NSCLC). Mutations, deletions, or other disruptions of LKB1 biological functions occur in 20-30% of NSCLC. Loss of LKB1 kinase activity impairs energy and metabolic stress sensing through the downstream AMPK and related kinase networks, deregulates mTOR signaling, promotes metabolic reprogramming, enhances oxidative stress, and therapy resistance. Functionally, LKB1 deficiency contributes to disrupted cell polarity, enhanced invasion and metastasis, altered tumor microenvironment and therapeutic resistance to radiotherapy and immune checkpoint inhibitors in NSCLC. Hence, understanding these LKB1 downstream targets and signaling pathways provides critical insight into how LKB1 loss rewires the tumor phenotypes. This review summarizes the LKB1 protein structure and domains, its regulatory mechanisms, and the diverse cellular functions that underpin its tumor-suppressor role in NSCLCs, therefore paving the road for novel therapeutic interventions to better treat NSCLC patients.