Our progress: With our previous NAISS Projects, we started elucidating how lipid scrambling, particularly PhosphatidylSerine (PS) can change the surface protein geometry (Schahl et al, Advanced Science, 2026). With this small grant, we would like to explore the generality of this concept to other proteins relevant to immunotherapies. We are confident that the data we will obtain with this feasibility study will be the basis for more comprehensive studies that will be crucial for understanding the immune system regulation by surface macromolecular interactions. Next steps: Monoclonal antibodies represent one of the most successful classes of modern therapeutics and form the foundation of many cancer, autoimmune, and infectious disease treatments. Current immunotherapeutic strategies are almost exclusively designed around protein targets, assuming that receptor accessibility and conformation are determined primarily by protein structure. However, emerging evidence demonstrates that membrane lipids are critical regulators of receptor organization, conformation, and accessibility. Our preliminary studies reveal that specific lipid environments can directly modulate the configuration of immune-cell surface proteins, thereby potentially altering their recognition by therapeutic antibodies. We hypothesize that membrane lipids constitute a hidden regulatory layer that controls therapeutic antibody binding to immune receptors. By systematically mapping lipid-protein interactions across immune cell surfaces and developing methods to manipulate these interactions, we aim to establish a new strategy for enhancing the efficacy of antibody-based therapies. This project will generate the first comprehensive atlas of immune receptor-lipid interactions, identify lipid signatures that govern receptor accessibility, and develop translational strategies to modulate membrane composition in vivo to improve therapeutic antibody engagement. What do we compute for: We will use this computational resource (i) for analyzing spatial surface proxiome map of immune cells and (ii) to generate molecular dynamics simulations of lipid-protein interactions based on those results. Initial application will be for small computing time for feasibility which will be followed by larger time applications. Impact: We are confident that with out previous computing results, we just started exploring the regulation of immune cell activity via protein-lipid interactions. With this study, we aim to transform our understanding of immune surface physiology via macromolecular interactions.