Research

The Li lab combines chemistry, biochemistry, immunology, and physiology to uncover fundamental mechanisms of our first line of defense against pathogens and cancer: innate immunity. Activation of innate immunity is a proven therapeutic strategy for vaccination, viral infection, and cancer, while inhibition is a strategy for treating autoimmune diseases and neurodegeneration. We explore the novel chemistry of these pathways to understand and develop new therapeutic targets and drugs that can manipulate innate immune activation with precision.

Cell-Specific Molecular Mechanisms

The innate immune STING pathway senses cytosolic dsDNA and generates the second messenger cGAMP, which activates STING to initiate downstream immune signaling. It exists in a delicate balance: it must detect and defend against viruses and cancer but not aberrantly respond to benign self dsDNA. We previously discovered that cGAMP is an immunotransmitter that is secreted by producing cells and detected by various immune cell types and stromal cells. We investigate cell type-specific cGAMP and STING regulation using chemical biology and genetic approaches, and discover new, potentially druggable checkpoints on the pathway.

Biochemical Mechanisms

We use classic biochemistry, structural biology, and medicinal chemistry to investigate at the atomic level how protein and small molecule immunomodulators of the STING pathway function effectively and how they fall into dysregulation and cause inflammation. In parallel, we develop and refine prototype drugs that bind to targets in the STING pathway and can be used to test therapeutic hypotheses in disease models.

Immunological Disease Models

Cancer and autoimmunity are two sides of the same coin of STING physiology. We have strong interest in the balancing act of the STING pathway in whole organisms. We rely heavily on mouse genetic models and are building cutting-edge genetic knock-in mouse strains that selectively perturb regulators that we have uncovered. We use these mouse strains coupled with cancer, infection, and autoimmune disease models to contextualize the roles of each regulator in different disease settings. We also use these disease models to test our therapeutic hypotheses and lead compounds.