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Abstract
Cellular function relies on the spatial organization of proteins, and shifts in localization patterns are hallmarks of diseases. Modern proteomics is steadily advancing efforts to identify proteomes with their spatial contexts to understand disease onset and progression. Microscopy provides high-resolution insights into protein localizations, and mass spectrometry delivers wider coverage of the proteome. The integration of optical precision with mass spectrometry is thus crucial for uncovering how spatial localizations drive diseases or therapeutic response. In this review, we highlight cutting-edge photo- proteomic approaches such as μMap, STOMP, and optoproteomics that integrate photolabeling with proteome discovery to achieve a nanometer-scale interactome. These tools now enable high-resolution mapping of proteome organization and open new directions in in vitro, in vivo, FFPE tissue, and computationally integrated spatial proteomics. Developments in photocatalyst chemistry, automated photolabeling workflows, and computational frameworks for integrating imaging and proteomic data from cultured cells to complex tissues pave the way to transform spatial proteomics into a powerful platform for detecting disease and its trajectory.