ORIGINAL RESEARCH article
Front. Immunol.
Sec. Molecular Innate Immunity
This article is part of the Research TopicRegulation of Innate Immunity Response: from Drosophila to HumansView all 8 articles
STING Activation by Teniposide: A Potential Direct Mechanism Beyond cGAS stimulation
Provisionally accepted
Estanislao Nistal-Villan1*
Javier Arranz-Herrero1
Laura Marquez-Cantudo1
Ruben M Buey2
Adrian Velazquez-Campoy3
Vicent Tur-Planells1
Adolfo García-Sastre4
Lisa Miorin4
Sergio Rius-Rocabert1
Beatriz De Pascual-Teresa1
Claire Coderch1*- 1CEU San Pablo University, Madrid, Spain
- 2Universidad de Salamanca, Salamanca, Spain
- 3Universidad de Zaragoza, Zaragoza, Spain
- 4Icahn School of Medicine at Mount Sinai, New York, United States
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The STimulator of Interferon Genes (STING) is a key adaptor protein in the innate immune response to cytosolic DNA, making it a promising therapeutic target. Identifying novel STING ligands could provide new opportunities for immune modulation. In this study, we employed high-throughput virtual screening and identified Teniposide, an anticancer drug used primarily for infant leukemia, as a direct STING ligand. We demonstrate that Teniposide activates the IFN-β signaling pathway in a STING-dependent manner, that does not require dsDNA sensors cyclic GMP-AMP synthase (cGAS) and Interferon Gamma Inducible Protein 16 (IFI16). Direct binding of Teniposide to STING's cytosolic domain was confirmed via isothermal titration calorimetry (ITC), further supported by a double mutant STING variant unable to bind Teniposide. Computational docking and molecular 2 dynamics simulations revealed a symmetrical binding mode, with two Teniposide molecules interacting with STING. These results suggest that Teniposide may potentially activate STING through a previously unrecognized, cGAS-independent mechanism, in addition to potential cGAS-STING effects via canonical stimulation. Our combined computational and experimental evidence supports its repurpose as a STING agonist, highlighting new therapeutic possibilities for innate immune stimulation.
Keywords: cdiAMPs, cdiGAMPs, cdiGMPs, CDNs, CGAMP, CGAS, Cyclic dinucleotides, cyclic di-nucleotides
Received: 01 Aug 2025; Accepted: 29 Nov 2025.
Copyright: © 2025 Nistal-Villan, Arranz-Herrero, Marquez-Cantudo, Buey, Velazquez-Campoy, Tur-Planells, García-Sastre, Miorin, Rius-Rocabert, De Pascual-Teresa and Coderch. 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:
Estanislao Nistal-Villan
Claire Coderch
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