Researchers have long focused on the Stimulator of Interferon Genes (STING) pathway, a key component of the innate immune system, as an approach to recruit immune cells to target cancer. However, stimulation of the pathway can also exacerbate many inflammatory diseases, emphasizing a need for therapeutic STING inhibition. No STING investigational drugs have advanced into clinical trials due to limited understanding of the pathway’s biochemical mechanisms.
In a new study published in Nature Chemical Biology titled “Cysteine allostery and autoinhibition govern human STING oligomer functionality,” researchers from the Arc Institute have revealed key differences in STING inhibition between humans and mice to improve STING translational therapeutic research.
Led by Lingyin Li, PhD, core investigator at the Arc Institute and professor at Stanford University, the study evaluated the effectiveness of H-151, an irreversible antagonist of STING that targets cysteine 88 and cysteine 91 in the transmembrane region of both mouse and human STING. H-151 has shown promise in reversing cognitive decline in mice but failed to block human STING signaling in purified human blood cells.
Results showed that the target site of H-151 in humans lacks a pocket that is found in mouse STING. The mechanistic difference explains the discrepancies in inhibitor effectiveness between the two species, highlighting the limitations of using mouse models to predict human outcomes in STING-targeted therapy development.
“This work emphasizes the need to focus on developing STING inhibitors exclusively in humans,” said Xujun Cao, PhD, co-first author on the paper and a postdoctoral fellow in the Li Lab. “Our method for uncovering this distinct druggable pocket provides a blueprint for others seeking to identify context-independent targets that can prevent STING autoimmunity.”
STING oligomerization is an essential checkpoint prior to triggering immune activation. Inactive STING exists as a stable dimer auto-inhibited by its C-terminal tail (CTT). Results showed that cysteine 91 (C91) palmitoylation, a reversible post-translational modification that attaches a palmitoyl group, is not universally necessary for human STING signaling. The authors identified a new human STING palmitoylation site at cysteine 64 (C64) that prevents basal inactive oligomer formation to regulate STING activation.
“For STING to function, it needs to oligomerize flawlessly,” said Rebecca Chan, another co-first author of the paper and a former graduate student in the Li Lab. “This discovery reveals why STING activation has such a high threshold—if it were easy to activate, our immune system would be attacking our own cells all the time. It’s an exquisitely controlled process, which is actually a good thing.”
Additionally, the effects of palmitoylation at C64 and C91 converge on the control of intradimer disulfide bond formation at cysteine 148. The dynamic equilibria of these cysteine post-translational modifications allow proper STING ligand-binding domain self-assembly and scaffolding function.
Due to limitations of targeting these cysteines, the authors proposed an alternative therapeutic strategy that harnesses STING’s own autoinhibition mechanism and identified an eight-amino-acid peptide, using a minimal sequence of its CTT, that inhibits signaling by binding a defined pocket at the oligomerization interface.
Looking ahead, the researchers will explore whether this understanding of STING inhibition could expand treatment possibilities beyond cancer immunotherapy, such as neurodegeneration and autoimmune diseases. They will also continue the development of these molecular candidates as human-ready STING inhibitors for future clinical trials.
The post STING Inhibition Differences Revealed Between Humans and Mice appeared first on GEN - Genetic Engineering and Biotechnology News.
In a new study published in Nature Chemical Biology titled “Cysteine allostery and autoinhibition govern human STING oligomer functionality,” researchers from the Arc Institute have revealed key differences in STING inhibition between humans and mice to improve STING translational therapeutic research.
Led by Lingyin Li, PhD, core investigator at the Arc Institute and professor at Stanford University, the study evaluated the effectiveness of H-151, an irreversible antagonist of STING that targets cysteine 88 and cysteine 91 in the transmembrane region of both mouse and human STING. H-151 has shown promise in reversing cognitive decline in mice but failed to block human STING signaling in purified human blood cells.
Results showed that the target site of H-151 in humans lacks a pocket that is found in mouse STING. The mechanistic difference explains the discrepancies in inhibitor effectiveness between the two species, highlighting the limitations of using mouse models to predict human outcomes in STING-targeted therapy development.
“This work emphasizes the need to focus on developing STING inhibitors exclusively in humans,” said Xujun Cao, PhD, co-first author on the paper and a postdoctoral fellow in the Li Lab. “Our method for uncovering this distinct druggable pocket provides a blueprint for others seeking to identify context-independent targets that can prevent STING autoimmunity.”
STING oligomerization is an essential checkpoint prior to triggering immune activation. Inactive STING exists as a stable dimer auto-inhibited by its C-terminal tail (CTT). Results showed that cysteine 91 (C91) palmitoylation, a reversible post-translational modification that attaches a palmitoyl group, is not universally necessary for human STING signaling. The authors identified a new human STING palmitoylation site at cysteine 64 (C64) that prevents basal inactive oligomer formation to regulate STING activation.
“For STING to function, it needs to oligomerize flawlessly,” said Rebecca Chan, another co-first author of the paper and a former graduate student in the Li Lab. “This discovery reveals why STING activation has such a high threshold—if it were easy to activate, our immune system would be attacking our own cells all the time. It’s an exquisitely controlled process, which is actually a good thing.”
Additionally, the effects of palmitoylation at C64 and C91 converge on the control of intradimer disulfide bond formation at cysteine 148. The dynamic equilibria of these cysteine post-translational modifications allow proper STING ligand-binding domain self-assembly and scaffolding function.
Due to limitations of targeting these cysteines, the authors proposed an alternative therapeutic strategy that harnesses STING’s own autoinhibition mechanism and identified an eight-amino-acid peptide, using a minimal sequence of its CTT, that inhibits signaling by binding a defined pocket at the oligomerization interface.
Looking ahead, the researchers will explore whether this understanding of STING inhibition could expand treatment possibilities beyond cancer immunotherapy, such as neurodegeneration and autoimmune diseases. They will also continue the development of these molecular candidates as human-ready STING inhibitors for future clinical trials.
The post STING Inhibition Differences Revealed Between Humans and Mice appeared first on GEN - Genetic Engineering and Biotechnology News.