The dual face of reprogrammed proteostasis in cancer and its epigenetic regulation: A survival option and a therapeutic opportunity.

Proteostasis is essential for cellular homeostasis and is maintained through an integrated network encompassing the unfolded protein response (UPR), molecular chaperones such as heat shock proteins (HSPs), and degradative systems including the ubiquitin-proteasome and autophagy-lysosomal pathways. In cancer, microenvironmental stresses such as hypoxia, nutrient deprivation, and oxidative imbalance impose a persistent proteotoxic burden, driving a context-dependent rewiring of these pathways that supports tumor survival, plasticity, and progression. Increasing evidence indicates that the functional outcomes of proteostasis responses, whether adaptive or cytotoxic, are determined by specific molecular cues, including the intensity and duration of stress, pathway crosstalk, and cell-intrinsic oncogenic alterations. Epigenetic mechanisms, comprising DNA methylation, histone modifications, and non-coding RNAs, further fine-tune these proteostatic programs by modulating the expression and activity of key regulators, thereby contributing to drug resistance but also generating cancer-selective vulnerabilities. This review provides a structured and mechanistic overview of how UPR, chaperone networks, and protein degradation pathways are remodeled in cancer and examines the epigenetic determinants that shape their adaptive behavior. Finally, we discuss emerging translational opportunities arising from the dual role of proteostasis in cancer, highlighting therapeutic strategies that exploit the dynamic interplay between proteostatic and epigenetic regulation.