Our Research & Initiatives
The Wu Lab at Scripps Research, Department of Molecular and Cellular Biology, is interested in advancing the understanding of immune responses towards cancer and human pathogens. Our research integrates synthetic chemistry with glycobiology to explore the cellular and molecular mechanisms underlying these processes.
Research in our laboratory integrates synthetic chemistry with glycobiology to explore the cellular and molecular mechanisms that control immune responses to cancer and human pathogens. We focus on developing chemoenzymatic tools to study these processes and engineer the cell surface of immune cells for therapeutic applications.
Our early work focused on the development of chemical tools to investigate the relevance of protein glycosylation in human disease. The glycome, the complete set of glycans produced by a cell, regulates key physiological processes such as angiogenesis, fertilization, stem cell development, and neuronal function. Glycosylation changes serve as informative biomarkers for cancer and inflammation. Unlike proteins and nucleic acids, glycans are not directly encoded by the genome but are synthesized through stepwise enzymatic reactions. As a result, traditional genetic and biochemical approaches alone cannot fully characterize the glycome. To address this challenge, we develop complementary chemical tools for both “bottom-up” and “top-down” glycan analysis. Two key chemical tools developed by my lab are:
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Biocompatible copper catalysts for Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC)—a cornerstone of click chemistry—enabling proteomic analysis and in vivo biomolecule labeling, now widely adopted by over 200 labs worldwide.
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Chemoenzymatic methods for detecting and modifying cell-surface glycans, facilitating functional studies and therapeutic applications.
These tools have enabled glycan imaging in living organisms, led to the discovery of novel disease biomarkers, and opened new therapeutic avenues. Major discoveries enabled by these tools include:
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The discovery of fucosylated glycans as alternative receptors for influenza virus, expanding the known set of host-virus interactions beyond sialylated glycans.
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Increased N-glycan α1,3-fucosylation enhances Wnt co-receptor Lrp6 endocytosis, suppressing Wnt-β-catenin signaling.
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Mutation of the cloche gene reduces fucosylation in zebrafish embryogenesis. Supplementing fucose or GDP-fucose partially rescues this defect, significantly extending mutant lifespans.
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A 13-fold decrease in N-acetyllactosamine (LacNAc) expression in early-stage lung adenocarcinoma, suggesting LacNAc as a potential early diagnostic marker.
In these studies, we discovered that H. pylori α1-3-fucosyltransferase exhibits an unexpected donor substrate flexibility: it can transfer macromolecules—such as a full-length antibody—onto LacNAc residues in the glycocalyx of live cells when the antibody is conjugated to the enzyme’s natural donor substrate GDP-fucose. This reaction is rapid, quantitative, and minimally perturbative to cellular function, representing the first example of a glycosyltransferase capable of transferring a protein-linked nucleotide sugar donor. Leveraging this property, we developed a simple, cost-effective method to construct antibody–cell conjugates (ACCs) using primary immune cells or NK-92MI cells, which are under clinical evaluation as “off-the-shelf” cancer immunotherapies. By attaching the HER2 antibody Herceptin to NK-92MI cells, we endowed them with target specificity and achieved potent lysis of HER2⁺ cancer cells ex vivo and in vivo. This chemoenzymatic strategy provides a rapid, modular alternative to genetic engineering for cellular therapy design.
From the above studies, we found ourselves in a unique position to contribute new tools that would propel the field of immunobiology, and this has been the theme of our group at Scripps since 2015. We are developing chemical tools to explore the cellular and molecular mechanisms that control immune responses toward cancer and human pathogens with a focus on the following unsolved problems in immunology: What are the compositions and properties of tumor-specific antigen (TSA)-reactive and bystander tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment? How to address the on-target, off-tumor toxicity of chimeric antigen receptor (CAR)-T cells? Can we enhance effector function and longevity of T cells for treating chronic infection and cancer? And how to overcome the immunosuppressive tumor microenvironment to treat solid tumors?
