The complexity and pharmacological modulation of TBK1 signaling in cancer

TBK1 (TANK-binding kinase 1) is a serine/threonine kinase that regulates many critical cellular processes including immune responses, metabolism, and autophagy. Dysregulated TBK1 activity is implicated in immunological and metabolic pathologies, and plays a prominent role in the development and progression of diverse cancers. Notably, TBK1 exhibits context-dependent functions, exerting both protumor and antitumor effects depending on tumor type as well as microenvironmental and possibly spatiotemporal conditions. TBK1 integrates signaling pathways that regulate both cancer cells and immune responses within the TME (tumor microenvironment). Despite promising preclinical data, the clinical translation of TBK1-targeted therapies remains challenging due to its functional complexity. In this review, we discuss the molecular mechanisms underlying TBK1 functions, with a focus on its roles in cancer biology and immune regulation, and evaluate current and potential therapeutic strategies targeting TBK1.