Light-driven spatial proteomics: Photocatalytic strategies for mapping protein microenvironments

Modern proteomic efforts aim to define protein composition and protein-protein interactions within native spatial tissue contexts to understand disease mechanisms and therapeutic responses. Two complementary strategies dominate this effort: physically resolved mapping using high-plex imaging, mass cytometry, or laser-capture microdissection, and chemically defined spatial proteomics based on enzyme or photo-proximity-mediated labeling. Photo-proximity labeling enables nanometer-scale mapping of protein neighborhoods with precise spatial control, overcoming limitations of enzyme-based approaches. This review highlights emerging light-driven spatial proteomic technologies, including targeted photocatalytic labeling and optically guided microproteomics, that combine optical precision with deep proteome coverage to generate high-resolution interactome maps. These methods enable analysis of molecular organization across in vitro and in vivo systems, including formalin-fixed, paraffin-embedded tissues, and reveal disease-relevant molecular reorganization. We discuss recent advances in photo-proteomic strategies that provide mechanistic insight into protein organization in patient tissues and support biomarker discovery in cancer, neurodegeneration, and other complex diseases.