Key Differences in STING Inhibition Between Humans and Mice Uncovered by Researchers

Recent research has shed light on the fundamental differences in the STING (Stimulator of Interferon Genes) pathway between humans and mice, unveiling challenges in developing effective STING-targeted therapies. The study, published in Nature Chemical Biology, was led by biochemist Lingyin Li from the Arc Institute. The STING pathway plays a crucial role in the immune response against pathogens and has been a focal point in cancer immunotherapy, primarily through activation to recruit immune cells. However, the new findings emphasize that inhibiting this pathway in humans presents unique hurdles.

Historically, much of the research on STING has focused on its activation to stimulate immune responses, but overactivation can also damage healthy cells, indicating a need for precise regulation. The study evaluated H-151, a potent inhibitor designed for human STING, which successfully reversed cognitive decline in mice but failed to inhibit human STING signaling in purified human blood cells. The team discovered that a critical target site in mouse STING, which H-151 binds to effectively, lacks a similar pocket in human STING, making drug design for humans more complex.

To address this, researchers dissected the signaling mechanics of human STING, finding that oligomerization—where STING molecules assemble into larger complexes—acts as a key activation checkpoint. By mimicking STING's natural autoinhibitory mechanisms, the team developed prototype molecules that prevent oligomerization, potentially offering new avenues for therapeutic development. This approach aims to create human-specific STING inhibitors, essential for avoiding adverse effects caused by overactivation.

The study highlights the importance of focusing on human-specific pathways when designing drugs, especially for immune modulation processes. It also provides a blueprint for identifying druggable pockets that can be targeted independent of species-specific differences, advancing the possibilities for treatments beyond cancer, including neurodegeneration and autoimmune diseases.

Looking forward, Li’s team plans to explore these findings' implications across various conditions and develop promising molecular candidates suitable for future clinical trials, emphasizing the need for human-centered drug development strategies in immunotherapy.