Authors
Wei Zhou, Xiangyu Wang, Susanne S Steigleder, Aowei Xing, Dan Yang, Zhuoyue Li, Hongji Liu, Yuxin Zhang, Wenjing Wang, Feiyang Shen, Yihan Tang, Lin Deng, Hui Jiang
Published in
Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 33. Pages e2533402123. Aug 18, 2026. Epub Aug 14, 2026.
Abstract
Inflammation exerts context-dependent influences on tumor progression and therapeutic response. Although chemotherapy remains a cornerstone of cancer treatment, its functional interplay with inflammatory signaling is still incompletely understood. Here, we identify TANK-binding kinase 1 (TBK1) as a critical modulator of chemotherapeutic efficacy through its impact on DNA damage repair. TBK1 activation potentiates cancer-cell death induced by chemotherapeutic agents by promoting DNA damage and impairing homologous recombination (HR) repair. This effect occurs independently of canonical inflammatory cytokines, as demonstrated in IRF3- and p65- double deficient cells. Mechanistically, TBK1 suppresses recruitment of the key HR factor Meiotic Recombination 11 Homolog 1 (MRE11) to PARP1 at DNA-damage sites in a kinase-activity-dependent yet cytokine-independent manner. Furthermore, TBK1 activation correlates with enhanced p53 signaling and genomic instability, providing a molecular basis for its pro-death effects under chemotherapy. Collectively, these findings reveal a previously unrecognized function of TBK1 in modulating the DNA-damage response, linking inflammatory signaling to genome destabilization and identifying the TBK1-MRE11 axis as a potential target to enhance chemotherapeutic efficacy.
PMID:
42599782
Bibliographic data and abstract were imported from PubMed on 15 Aug 2026.
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