Proteostasis Deregulation by Metabolism Drives the Hallmarks of Cancer

Cancer cells acquire hallmark behaviors through adaptations that extend beyond genetic and epigenetic changes. Proteostasis-the biochemical network governing protein synthesis, folding, trafficking, and degradation-is a fundamental, yet underappreciated, mediator of these adaptations that merits consideration as a hallmark-enabling mechanism. Metabolic alterations impose proteotoxic stress, globally rewire protein homeostasis, and selectively modulate key oncogenic and tumor suppressive proteins. A unifying framework is proposed wherein metabolic deregulation of proteostasis operates throughout carcinogenesis: early, by enhancing accumulation of premalignant clones bearing cancer-driving somatic mutations in response to environmental and systemic metabolic stress, and later, by buffering proteotoxic stress to sustain malignant growth in hostile tissue environments. This perspective connects cancer risk with genetic background, diet, microbiome-derived metabolites, and metabolic disease, introduces metabolic bypass of tumor suppression as an alternative to classical genetic models, and highlights the metabolism-proteostasis interface as a promising target for cancer prevention and therapy.