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Distinct HSP families, including HSP27, HSP60, HSP70, HSP90, and HSP110, promote malignant progression through complementary effects on apoptosis regulation, mitochondrial function, proteostasis, and stabilization of oncogenic signaling pathways. This makes HSPs attractive therapeutic targets. Their coordinated roles within stress-adaptive chaperone networks further garner interest in targeting multiple HSP families in cancer therapy. Discussion: Preclinical and clinical studies have established multiple HSP families as promising anticancer targets; however, clinical translation of HSP-directed therapies has been challenged by toxicity, compensatory heat shock responses, and resistance mechanisms. Many N-terminal HSP90 inhibitors have shown clinical utility but have also highlighted the need for alternative approaches, including C-terminal inhibition, HSP70-directed therapies, and rational combination strategies targeting compensatory survival pathways. Emerging inhibitors targeting HSP27, HSP60, and HSP110, as well as HSP-based vaccines, further expand therapeutic opportunities across cancer subtypes. Collectively, these approaches highlight the growing therapeutic relevance of disrupting interconnected HSP networks rather than targeting individual chaperones in isolation. Conclusions: Future development of heat shock protein-targeted therapies will require a deeper understanding of HSP-mediated chemoresistance. Clinical trial and drug development approaches may benefit from combination or multi-targeted strategies that simultaneously disrupt multiple components of the heat shock protein network to achieve more durable anticancer responses.<\/jats:p>","DOI":"10.3390\/jcm15103605","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T19:10:52Z","timestamp":1778267452000},"page":"3605","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Heat Shock Proteins as Targets for Cancer Therapeutics"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7739-4919","authenticated-orcid":false,"given":"Aryaman","family":"Trikala","sequence":"first","affiliation":[{"name":"School of Medicine, California University of Science and Medicine, Colton, CA 92324, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binghui","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Cancer Genetics & Epigenetics, Beckman Research Institute, City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharonlin","family":"Bhardwaj","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, City of Hope Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3267207","DOI":"10.1155\/2019\/3267207","article-title":"Heat Shock Proteins in Cancer Immunotherapy","volume":"2019","author":"Das","year":"2019","journal-title":"J. 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