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This Review integrates structural, biochemical, preclinical, and clinical evidence on HSP90, HSP70, HSP60, HSP40, HSP110, and small HSPs. We explain how ATPase cycles, chaperonin cages, co\u2010chaperone networks, and organelle\u2010specific localization stabilize metabolic enzymes, glucose transporters, hypoxia\u2010responsive factors, and electron\u2010transport\u2010chain components, thereby coordinating glycolysis, mitochondrial bioenergetics, redox homeostasis, lipid metabolism, and metabolic plasticity. These mechanisms enable tumor survival and therapy resistance but also create context\u2010dependent vulnerabilities. We critically evaluate pan\u2010HSP and isoform\u2010selective inhibitors, disruption of chaperone\u2010client or co\u2010chaperone interfaces, HSP\u2010directed immunotherapies, and biomarker\u2010guided combinations with metabolic or immune therapies. Clinical translation remains limited by systemic toxicity, compensatory heat\u2010shock responses, tumor\u2010type heterogeneity, and the absence of validated predictive biomarkers. We also assess circulating HSPs, cryo\u2010EM analysis of chaperone complexes, and AI\u2010assisted ligand design as routes for biomarker development and selective drug discovery. By linking chaperone architecture and client specificity to metabolic outputs and cancer phenotypes, this Review establishes a framework for differentiating actionable HSP dependencies from observational associations. It further defines priorities for patient stratification and precision oncology, supporting the development of selective and tractable strategies that target proteostasis\u2013metabolism coupling.<\/jats:p>","DOI":"10.1002\/mco2.70966","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T06:51:12Z","timestamp":1789195872000},"source":"Crossref","is-referenced-by-count":1,"title":["Heat Shock Proteins in Cancer: Mechanisms and Therapeutic Targeting"],"prefix":"10.1002","volume":"7","author":[{"given":"Sheng","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Urology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan China"},{"name":"Hubei Provincial Clinical Research Center for Minimally Invasive Treatment of Urology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen\u2010Qian","family":"Liu","sequence":"additional","affiliation":[{"name":"Laboratory of 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