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By promoting protein folding and facilitating the functional activation of a broad repertoire of clients, HSP90 underpins essential cellular processes, including development, proliferation, differentiation, and stress responses. In cancer, this extensive network renders tumor cells highly dependent on HSP90 to maintain oncogenic signaling, tolerate proteotoxic stress, and survive therapeutic insults. In this review, we propose an integrated conceptual framework linking HSP90's molecular chaperone functions to its pathological roles in cancer: HSP90 serves as a central node that concurrently supports oncogenic signaling, buffers proteotoxic stress, maintains cancer stem cell plasticity, and shapes tumor\u2010immune interactions\u2010all of which converge to drive therapeutic resistance and tumor recurrence. Within this framework, we summarize the molecular mechanisms governing HSP90 activity and dissect its context\u2010dependent roles in cancer progression, drug resistance, and immune regulation. We further highlight recent advances in HSP90\u2010targeted interventions, including small\u2010molecule inhibitors, monoclonal antibodies, engineered immune cells, and emerging strategies designed to prevent, delay, or overcome drug resistance. Taken together, these developments underscore HSP90 as a versatile therapeutic node and point toward innovative, resistance\u2010aware strategies for clinical translation and future research.<\/jats:p>","DOI":"10.1002\/advs.75895","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T08:43:26Z","timestamp":1780476206000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Heat Shock Protein 90: From Molecular Chaperone Function to Therapeutic Targeting in Malignancies"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7231-360X","authenticated-orcid":false,"given":"Beibei","family":"Zhang","sequence":"first","affiliation":[{"name":"Institute of Biomedical Research Yunnan University  Kunming Yunnan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinxin","family":"Zou","sequence":"additional","affiliation":[{"name":"Institute of 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