Spatial protein interactomics in solid primary human tissue

Protein-protein interactions (PPIs) in diseased tissues represent a promising class of potential drug targets. However, PPIs are typically identified in live cells, lysate, and genetically engineered model organisms, limiting their translational value to human disease. Here we describe MAP-IT, an optimized photocatalytic carbene-based proximity labeling method for direct PPI mapping in primary human tissue sections, which bypasses the need for model organisms in the initial discovery step. We use MAP-IT to profile PPIs in situ for cell surface and nuclear target proteins, identify and orthogonally validate new interactors of EGFR in colon cancer, and couple light-powered MAP-IT labeling with spatially patterned visible light irradiation guided by neural network image segmentation to map location-specific protein interactomes. Protein-protein interactions (PPIs) represent a promising class of drug targets. Here, the authors describe MAP-IT, a photocatalytic carbene-based proximity labeling method for direct PPI mapping in primary human tissue sections.