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The Janus-faced role of TBK1 in health and disease: balancing immune defense and pathological progression

Year: 2026
Type: review
Abstract: TANK-binding kinase 1 (TBK1) is a central innate immune kinase that links pathogen recognition to type I interferon production. However, accumulating evidence indicates that its functions extend beyond canonical antiviral signaling to autophagy, mitochondrial quality control, cellular metabolism, cell survival, and cell death. Here, we review the multifaceted roles of TBK1 under physiological and pathological conditions, with emphasis on infectious diseases, cancer, and other non-infectious diseases. During infection, TBK1 integrates signals from multiple pattern recognition receptors to activate IRF3- and NF-κB-dependent host defenses, while diverse pathogens evade immunity by targeting TBK1 or its associated signaling complexes. In cancer, TBK1 exhibits context-dependent effects by supporting tumor cell survival and stress adaptation while also promoting antitumor immunity downstream of STING. Dysregulated TBK1 signaling is further implicated in neurodegenerative, autoinflammatory, and chronic inflammatory diseases, in which either TBK1 activation or loss of function can contribute to pathology. Collectively, these findings indicate that TBK1 should not be simply classified as protective or pathogenic. Its biological outputs are determined by cell type, upstream stimuli, molecular interaction networks, and the spatiotemporal state of signaling. This functional plasticity makes TBK1 a promising but complex therapeutic target. Rather than generalized inhibition or activation, future TBK1-targeted strategies should consider disease mechanisms and cell-specific contexts to achieve precise therapeutic modulation.
DOI: 10.3389/fimmu.2026.1995184
Language: English
Subfield: Immunology
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7223171221
FWCI:
Cites: 46
Cited by:
Related to: 10