TBK1

Overview

TBK1 (TANK-binding kinase 1) is a serine/threonine kinase that is a central effector of the cGAS-STING innate immune signaling axis. Upon activation by cytosolic DNA (e.g., from ruptured micronuclei), the cGAS-STING-TBK1 cascade drives phosphorylation of IRF3/IRF7 and production of type I interferons. In HGSOC precursors, TBK1 activation (evidenced by phospho-TBK1 positivity in CyCIF) is implicated as the upstream trigger of a constitutive IFN response that begins as early as the p53 signature stage.

Alterations observed in the corpus

  • Phospho-TBK1 (p-TBK1)-positive epithelial cells are detected in fallopian tube precursor lesions (p53.I, STIC.I, STIC.C) and invasive HGSOC by CyCIF and 3D CyCIF, with stepwise increase from ~22% of epithelial cells in p53.I to ~43% in STIC.C PMID:39386723.
  • p-TBK1 strongly co-localizes with p-STAT1, p-STAT3, and HLA-E within individual cells (pairwise odds ratios 1.5–50), consistent with active cGAS-STING-TBK1 signaling propagating the IFN/antigen-presentation program PMID:39386723.
  • cGAS protein is observed to be recruited to BANF1+ ruptured micronuclei in STIC.I epithelium by 3D CyCIF, implicating chromosomal instability-driven micronuclear rupture as the trigger for TBK1 activation PMID:39386723.

Cancer types (linked)

  • HGSOC — the cGAS-STING-TBK1 axis is activated in HGSOC precursors starting at the p53 signature stage; activation is independent of BRCA1/BRCA2 germline status PMID:39386723.

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • TBK1 is not a direct therapeutic target in this corpus. The cGAS-STING-TBK1 pathway is proposed as a mechanistic link between chromosomal instability and IFN-driven immune sculpting in HGSOC precursors; downstream HLA-E overexpression is the proposed therapeutic target via anti-NKG2A antibodies (e.g., monalizumab) rather than TBK1 itself PMID:39386723.

Open questions

  • Whether TBK1 inhibition would suppress the IFN response in HGSOC precursors and thereby release or worsen immune suppression is not tested PMID:39386723.
  • The relative contribution of canonical (cytosolic DNA via micronuclei) vs. non-canonical TBK1 activation to sustained IFN signaling across the HGSOC progression axis is not resolved PMID:39386723.

Sources

This page was processed by crosslinker on 2026-05-04.