The Janus-faced role of TBK1 in health and disease: balancing immune defense and pathological progression
- 1Institute of Virology and AIDS Research, The First Hospital of Jilin University
- 2Department of Infectious Diseases, Infectious Diseases and Pathogen Biology Center, Key Laboratory of Organ Regeneration and Transplantation of The Ministry of Education, The First Hospital of Jilin University
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.
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BibTeX
@article{fu2026janusfaced,
title = {{The Janus-faced role of TBK1 in health and disease: balancing immune defense and pathological progression}},
author = {Jingyi Fu and Zhaolong Li},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1995184},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1995184/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The Janus-faced role of TBK1 in health and disease: balancing immune defense and pathological progression
AU - Jingyi Fu
AU - Zhaolong Li
PY - 2026
DA - 2026/10/22
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1995184
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1995184/full
AB - 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.
SN - 1664-3224
ER -