Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic
Emily N. Chin, Chenguang Yu, Vincent F. Vartabedian, Ying Jia, M. N. Satish Kumar, Ana M. Gamo, William F. Vernier, Sabrina H. Ali, Mildred Kissai, Daniel C. Lazar, Nhan Nguyen, Laura E. Pereira, Brent Benish, Ashley K. Woods, Sean B. Joseph, Alan Chu, Kristen Johnson, Philipp N. Sander, Francisco Martínez‐Peña, Eric Hampton, Travis S. Young, Dennis W. Wolan, Arnab K. Chatterjee, Peter G. Schultz, H. Michael Petrassi, John R. Teijaro, Luke L. Lairson
Abstract
Targeting STING for cancer therapy Activation of the STING (stimulator of interferon genes) protein by cyclic dinucleotide metabolites plays a critical role in antitumor immunity. The development of synthetic STING agonists is therefore being pursued as a strategy for cancer therapy, but the inherent instability of dinucleotides has limited current efforts. Pan et al. and Chin et al. identified stable STING agonists that act in a “closed” conformation similar to the natural STING ligand, cyclic guanosine monophosphate–adenosine monophosphate (see the Perspective by Gajewski and Higgs). The small molecules can be given orally—an advantage over previously developed STING agonists, which required intratumoral administration. After oral or systemic administration in mice, the agonists activated STING and diverse immune cell types to promote antitumor immunity. These studies represent progress toward clinically viable STING agonists for cancer immunotherapy. Science , this issue p. eaba6098 , p. 993 ; see also p. 921