ORIGINAL RESEARCH article
Front. Oncol.
Sec. Cancer Immunity and Immunotherapy
This article is part of the Research TopicCancer Immunity: From Immunosurveillance to Immune Escape and Therapeutic TargetingView all 7 articles
cGAS/STING-mediated upregulation of NKG2D ligands in LSCs contributes to enhanced sensitivity to NK cells
Provisionally accepted
- First Affiliated Hospital of Gannan Medical University, Ganzhou, China
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Natural killer (NK) cells-mediated immune surveillance is essential role for tumor recognition and elimination. The binding of NK group 2 member D (NKG2D) ligands to NKG2D receptor is sufficient to activate the NK cells' cytotoxicity against targeted cells. Here we reported that the inhibition of poly (ADP-ribose) polymerase 1 (PARP1) in leukemia stem cells (LSCs) induced the expression of NKG2D ligands through the activation of DNA damage response. Activated ataxia-telangiectasia mutated proteins (ATM) and ɣH2AX foci accumulation were observed under the treatment of PARP inhibitor, leading to the accumulation of damaged DNA. Subsequently, cyclic GMP-AMP synthase (cGAS) was activated, and stimulator of interferon gene (STING) was recruited to promote the downstream signal transduction via TANK-binding kinase-1 (TBK1) and transcription regulatory factor 3 (IRF3). However, the NKG2D ligands induced by PARP inhibitor was reduced in STING or IRF3-knockdown LSCs, indicating that STING and IRF3 were necessary for the regulation of NGK2D ligands in LSCs upon the DNA damage response. These data indicated that the DNA damage response-mediated cGAS/STING/TBK1/IRF3 signalling pathway played an essential role in modulating NKG2D ligands expression in LSCs.
Keywords: CGAS, DNA damage response, NK cells, NKG2D ligands, PARP1, STING
Received: 10 Dec 2025; Accepted: 09 Feb 2026.
Copyright: © 2026 Zhu, Ouyang, YiLin, Zhang and Zhu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Huifang Zhu
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