A recent study published in Nature Chemical Biology on July 3, 2025, led by biochemist Lingyin Li from Stanford University, reveals significant differences in the STING (Stimulator of Interferon Genes) pathway between humans and mice, which has critical implications for drug development in cancer treatment.

The research highlights that the target site for H-151, an advanced STING inhibitor, lacks a crucial pocket in human STING that is present in mouse STING, illustrating the challenges of using mouse models for human drug development.

Historically, research has focused on activating the STING pathway to enhance immune responses against tumors; however, recent findings suggest that inhibiting STING may be necessary to prevent the immune system from attacking healthy cells.

The study emphasizes that precise control of STING activation is essential to avoid autoimmunity, indicating a high threshold for activation in humans.

Li's team identified that oligomerization, the assembly of STING molecules, is crucial for immune signaling, and they proposed a new strategy to inhibit this process to prevent STING activation in humans.

They developed a proof-of-concept molecule that mimics STING's natural autoinhibitory mechanism, potentially paving the way for new human-specific STING inhibitors.

Looking ahead, Li's lab aims to explore the implications of STING inhibition not only for cancer treatment but also for neurodegenerative diseases and autoimmune disorders.

Co-author Xujun Cao emphasizes the importance of focusing on human STING inhibitors to prevent autoimmunity and to identify context-independent drug targets.

This research underscores the necessity of developing STING inhibitors specifically for human biology rather than relying on mouse models, which may not accurately reflect human responses.