Cancer cells are notorious for hijacking cellular stress pathways to survive hostile conditions and resist treatment. One of the most critical of these is the unfolded protein response (UPR), a quality-control system that normally eliminates damaged proteins but becomes a survival tool in tumors. This review argues that looking at single biomarkers of UPR activity is insufficient because tumors are spatially and temporally complex. Instead, the authors propose combining high-resolution spatial transcriptomics and single-cell multiomics to build comprehensive multigene UPR signatures. Layering in computational pathology and mechanobiology, this framework could map proteostatic states — how well different tumor regions manage protein quality — across many cancer types. The goal is better patient stratification and smarter treatment decisions, though prospective clinical validation remains essential.
