Macrophages transfer functional proteins to their surface during live-cell uptake.

A cell's proteome is assumed to reflect its transcriptional and translational activity. Macrophages regularly acquire xenobiotic material from neighboring cells, which is thought to result in degradation of the material. However, increasing lines of evidence suggest that not all taken up material is degraded and other transfer-like processes also occur. Field standard technologies are unable to rigorously report on precisely how and by whom the macrophage protein repertoire is altered during these interactions, leaving unresolved the extent to which nondegradative processes contribute to altered phenotypes. Here, we leveraged chemical tools and proteomics to show that intact target cancer cell surface proteins are transferred to the macrophage cell surface at functionally impactful levels in a manner associated with live-cell uptake. Widespread acquisition of proteins during cell uptake reengineers the macrophage cell surface proteome and is a transcriptionally silent, cell-nonautonomous process with the potential to alter metabolic uptake.