Hsp90 <i>pan</i> and Isoform-Selective Inhibitors as Sensitizers for Cancer Immunotherapy
The 90 kDa heat shock proteins (Hsp90) are molecular chaperones that regulate the stability and maturation of numerous client proteins implicated in the regulation of cancer hallmarks. Despite the potential of <i>pan</i>-Hsp90 inhibitors as anticancer therapeutics, their clinical develop...
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MDPI AG
2025-07-01
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| Online Access: | https://www.mdpi.com/1424-8247/18/7/1025 |
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| author | Shiying Jia Neeraj Maurya Brian S. J. Blagg Xin Lu |
| author_facet | Shiying Jia Neeraj Maurya Brian S. J. Blagg Xin Lu |
| author_sort | Shiying Jia |
| collection | DOAJ |
| description | The 90 kDa heat shock proteins (Hsp90) are molecular chaperones that regulate the stability and maturation of numerous client proteins implicated in the regulation of cancer hallmarks. Despite the potential of <i>pan</i>-Hsp90 inhibitors as anticancer therapeutics, their clinical development has been hindered by on-target toxicities, particularly ocular and cardiotoxic effects, as well as the induction of pro-survival, compensatory heat shock responses. Together, these and other complications have prompted the development of isoform-selective Hsp90 inhibitors. In this review, we discuss the molecular bases for Hsp90 function and inhibition and emphasize recent advances in isoform-selective targeting. Importantly, we highlight how Hsp90 inhibition can sensitize tumors to cancer immunotherapy by enhancing antigen presentation, reducing immune checkpoint expression, remodeling the tumor microenvironment, and promoting innate immune activation. Special focus is given to Hsp90β-selective inhibitors, which modulate immunoregulatory pathways without eliciting the deleterious effects observed with pan-inhibition. Preclinical and early clinical data support the integration of Hsp90 inhibitors with immune checkpoint blockade and other immunotherapeutic modalities to overcome resistance mechanisms in immunologically cold tumors. Therefore, the continued development of isoform-selective Hsp90 inhibitors offers a promising avenue to potentiate cancer immunotherapy with improved efficacy. |
| format | Article |
| id | doaj-art-dc1d10f00b4648bd85aa9e87312df899 |
| institution | DOAJ |
| issn | 1424-8247 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj-art-dc1d10f00b4648bd85aa9e87312df8992025-08-20T02:47:07ZengMDPI AGPharmaceuticals1424-82472025-07-01187102510.3390/ph18071025Hsp90 <i>pan</i> and Isoform-Selective Inhibitors as Sensitizers for Cancer ImmunotherapyShiying Jia0Neeraj Maurya1Brian S. J. Blagg2Xin Lu3Department of Biological Sciences, Boler-Parseghian Center for Rare Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USADepartment of Chemistry and Biochemistry, Warren Center for Drug Discovery, University of Notre Dame, Notre Dame, IN 46556, USADepartment of Chemistry and Biochemistry, Warren Center for Drug Discovery, University of Notre Dame, Notre Dame, IN 46556, USADepartment of Biological Sciences, Boler-Parseghian Center for Rare Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USAThe 90 kDa heat shock proteins (Hsp90) are molecular chaperones that regulate the stability and maturation of numerous client proteins implicated in the regulation of cancer hallmarks. Despite the potential of <i>pan</i>-Hsp90 inhibitors as anticancer therapeutics, their clinical development has been hindered by on-target toxicities, particularly ocular and cardiotoxic effects, as well as the induction of pro-survival, compensatory heat shock responses. Together, these and other complications have prompted the development of isoform-selective Hsp90 inhibitors. In this review, we discuss the molecular bases for Hsp90 function and inhibition and emphasize recent advances in isoform-selective targeting. Importantly, we highlight how Hsp90 inhibition can sensitize tumors to cancer immunotherapy by enhancing antigen presentation, reducing immune checkpoint expression, remodeling the tumor microenvironment, and promoting innate immune activation. Special focus is given to Hsp90β-selective inhibitors, which modulate immunoregulatory pathways without eliciting the deleterious effects observed with pan-inhibition. Preclinical and early clinical data support the integration of Hsp90 inhibitors with immune checkpoint blockade and other immunotherapeutic modalities to overcome resistance mechanisms in immunologically cold tumors. Therefore, the continued development of isoform-selective Hsp90 inhibitors offers a promising avenue to potentiate cancer immunotherapy with improved efficacy.https://www.mdpi.com/1424-8247/18/7/1025Hsp90 inhibitorsHsp90βGrp94isoform-selectivitycancer immunotherapytumor microenvironment |
| spellingShingle | Shiying Jia Neeraj Maurya Brian S. J. Blagg Xin Lu Hsp90 <i>pan</i> and Isoform-Selective Inhibitors as Sensitizers for Cancer Immunotherapy Pharmaceuticals Hsp90 inhibitors Hsp90β Grp94 isoform-selectivity cancer immunotherapy tumor microenvironment |
| title | Hsp90 <i>pan</i> and Isoform-Selective Inhibitors as Sensitizers for Cancer Immunotherapy |
| title_full | Hsp90 <i>pan</i> and Isoform-Selective Inhibitors as Sensitizers for Cancer Immunotherapy |
| title_fullStr | Hsp90 <i>pan</i> and Isoform-Selective Inhibitors as Sensitizers for Cancer Immunotherapy |
| title_full_unstemmed | Hsp90 <i>pan</i> and Isoform-Selective Inhibitors as Sensitizers for Cancer Immunotherapy |
| title_short | Hsp90 <i>pan</i> and Isoform-Selective Inhibitors as Sensitizers for Cancer Immunotherapy |
| title_sort | hsp90 i pan i and isoform selective inhibitors as sensitizers for cancer immunotherapy |
| topic | Hsp90 inhibitors Hsp90β Grp94 isoform-selectivity cancer immunotherapy tumor microenvironment |
| url | https://www.mdpi.com/1424-8247/18/7/1025 |
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