The unfolded protein response in precision oncology: from mechanisms to therapeutic opportunities

The unfolded protein response (UPR) is a fundamental stress pathway coopted in cancer, and it is thought to drive adaptation, tumor progression, and therapeutic resistance. While the analysis of 'single-effector' biomarkers within the tumor microenvironment often fails to capture its spatial, temporal, and cellular complexity, recent advances in high-resolution spatial transcriptomics and single-cell multiomics may enable a shift from static readouts toward more comprehensive multigene UPR signatures. This could help resolve proteostatic heterogeneity at unprecedented resolution. In this review, we provide a pan-cancer perspective on using these quantitative signatures to map proteostatic states. By combining cell biology, mechanobiology, and computational pathology, our proposed translational framework blends morphological hallmarks with multiomic UPR signatures. Although still requiring prospective clinical validation, this approach could improve patient stratification and treatment decisions, advancing the field of precision oncology.