HSP90 inhibition enhances cancer immunotherapy by upregulating interferon response genes
Open accessAbstract
T-cell-based immunotherapies are promising treatments for cancer patients. Although durable responses can be achieved in some patients, many patients fail to respond to these therapies, underscoring the need for improvement with combination therapies. From a screen of 850 bioactive compounds, we identify HSP90 inhibitors as candidates for combination with immunotherapy. We show that inhibition of HSP90 with ganetespib enhances T-cell-mediated killing of patient-derived human melanoma cells by their autologous T cells in vitro and potentiates responses to anti-CTLA4 and anti-PD1 therapy in vivo. Mechanistic studies reveal that HSP90 inhibition results in upregulation of interferon response genes, which are essential for the enhanced killing of ganetespib treated melanoma cells by T cells. Taken together, these findings provide evidence that HSP90 inhibition can potentiate T-cell-mediated anti-tumor immune responses, and rationale to explore the combination of immunotherapy and HSP90 inhibitors.
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The HSP90 inhibitor ganetespib, which also inhibits the Tex-PSR chaperone gp96, has been shown to promote ICB efficacy.
“In this regard, it is worth noting that the HSP90 inhibitor ganetespib, which also inhibits the Tex-PSR chaperone gp96, has been shown to promote ICB efficacy51.”
From Proteotoxic stress response drives T cell exhaustion and immune evasion (2025) · cites this paper as [51]
The Results section, “HSP90 inhibition potentiates immune checkpoint blockade therapy,” reports that ganetespib improved responses to anti-CTLA4 and anti-PD1 treatment in tumor-bearing mice. The Discussion identifies GP96 as an HSP90 paralog, but our copy does not establish that ganetespib inhibits GP96 or identify it as a Tex-PSR chaperone. (LLM, conf=0.88)
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Cites
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Proteotoxic stress response drives T cell exhaustion and immune evasion
Wang, Y., Ma, A., Song, N.-J., Shannon, A. E., Amankwah, Y. S., Chen, X., Wu, W., Wang, Z., Saadey, A. A., Yousif, A., et al. (2025) · Nature · doi:10.1038/s41586-025-09539-1 · Cited by 68 · see citing works
Immunotherapies targeting stimulatory pathways and beyond
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- Authors
- Mbofung, R. M., McKenzie, J. A., Malu, S., Zhang, M., Peng, W., Liu, C., Kuiatse, I., Tieu, T., Williams, L., Devi, S., Ashkin, E., Xu, C., Huang, L., Zhang, M., Talukder, A. H., Tripathi, S. C., Khong, H., Satani, N., Muller, F. L., Roszik, J., Heffernan, T., Allison, J. P., Lizee, G., Hanash, S. M., Proia, D., Amaria, R., Davis, R. E., & Hwu, P.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Synta Pharmaceuticals (United States) (US)
- Corresponding author
- Hwu, Patrick
- ORCID
- Venue
- Nature Communications
- Published
- 2017-09-06
- Volume
- 8
- Issue
- 1
- Pages
- 451-451
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5587668
- OpenAlex
- W2751738241
- Cited by
- 159
- References
- 6
- Citations by year
- 2026: 12 · 2025: 24 · 2024: 17 · 2023: 15 · 2022: 25 · 2021: 19 · 2020: 15 · 2019: 14 · 2018: 16 · 2017: 2
- FWCI
- 5.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Cancer Prevention and Research Institute of Texas (RP140106, P30CA016672, CPRIT RP140106)
- Melanoma Research Alliance
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (P30CA016672)
- AIM at Melanoma
- Aldeyra Therapeutics
- National Cancer Institute (P30CA016672, P50CA093459, R01CA187076)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- HSP90 inhibition, ganetespib, cancer immunotherapy, interferon response genes, T cell cytotoxicity, melanoma, anti-CTLA-4, anti-PD-1, combination therapy, high-throughput screening, antitumor immunity
- MeSH terms
- Ipilimumab, Animals, Female, Humans, Immunotherapy, Interferons, Melanoma, Mice, Inbred C57BL, T-Lymphocytes, Triazoles, Up-Regulation, Gene Expression Regulation, Neoplastic, HSP90 Heat-Shock Proteins, Gene Expression Profiling, Xenograft Model Antitumor Assays, Cell Line, Tumor, Tumor Burden, Kaplan-Meier Estimate
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