Breakthrough study questions longstanding STING activation approach

Researchers have long focused on the STING (Stimulator of Interferon Genes) pathway as a way to harness the immune system's natural defenses against cancer. This pathway, which plays a key role in helping the body defend against potential pathogens, can be leveraged to trigger an innate immune response that targets cancer cells. However, a study published July 3 in the journal Nature Chemical Biology, led by biochemist Lingyin Li (Bluesky: @lingyinli.bsky.social), is spearheading a new school of thought.

Historically, research on STING has overwhelmingly focused on activating the pathway to recruit immune cells that attack tumors. However, inhibiting the pathway is understudied and mounting evidence suggests that overactivation of STING may turn the immune system against healthy cells. This dual nature of activation and inhibition of STING make the pathway a powerful but complex target for drug development – one that has yet to be viable in humans.

"Our study evaluated the effectiveness of H-151, the most advanced inhibitor of human STING, which has shown promise in reversing cognitive decline in mice but has failed to block human STING signaling in purified human blood cells," said senior author Li, an Arc Institute Core Investigator and professor in the Biochemistry Department and ChEM-H Institute at Stanford University. "Our results show that in humans the target site of H-151 lacks a pocket that is found in mouse STING – without it, drug tailoring is incredibly challenging." 

H-151 is a powerful STING inhibitor because once it binds to its target, it does not let go. It also targets a section of the STING pathway that is necessary for mouse STING signalling, but not humans. This fundamental 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. 

To circumvent this mismatch, Li's team rigorously dissected the essential steps required for human STING signalling. The team found that oligomerization,the process where STING molecules assemble to trigger immune signaling, is an essential checkpoint prior to activation. Drawing inspiration from STING's natural autoinhibitory mechanism, Li's team proposed targeting STING by directly preventing oligomerization and developed a proof-of-concept molecule that mimics this mechanism and prevents STING from forming the large complexes necessary for immune activation in humans.

"This work emphasizes the need to focus on developing STING inhibitors exclusively in humans," says Xujun Cao, one of the first authors 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." 

"For STING to function, it needs to oligomerize flawlessly," says Rebecca Chan, the paper's other first author, 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."

Looking ahead,the Li lab will explore whether this understanding of STING inhibition could expand treatment possibilities beyond cancer immunotherapy. Their research will focus on potential applications for neurodegeneration and autoimmune diseases, while simultaneously advancing the development of promising molecular candidates as human-ready STING inhibitors for future clinical trials.