Publication Date
12-15-2023
Journal
iScience
DOI
10.1016/j.isci.2023.108308
PMID
38025772
PMCID
PMC10663837
PubMedCentral® Posted Date
10-24-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Microenvironment, Biological sciences, Molecular biology, Cancer
Abstract
Low response rates and immune-related adverse events limit the remarkable impact of cancer immunotherapy. To improve clinical outcomes, preclinical studies have shown that combining immunotherapies with N-terminal Hsp90 inhibitors resulted in improved efficacy, even though induction of an extensive heat shock response (HSR) and less than optimal dosing of these inhibitors limited their clinical efficacy as monotherapies. We discovered that the natural product Enniatin A (EnnA) targets Hsp90 and destabilizes its client oncoproteins without inducing an HSR. EnnA triggers immunogenic cell death in triple-negative breast cancer (TNBC) syngeneic mouse models and exhibits superior antitumor activity compared to Hsp90 N-terminal inhibitors. EnnA reprograms the tumor microenvironment (TME) to promote CD8+ T cell-dependent antitumor immunity by reducing PD-L1 levels and activating the chemokine receptor CX3CR1 pathway. These findings provide strong evidence for transforming the immunosuppressive TME into a more tumor-hostile milieu by engaging Hsp90 with therapeutic agents involving novel mechanisms of action.
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Biology Commons, Biomedical Informatics Commons, Medical Molecular Biology Commons, Neoplasms Commons, Oncology Commons
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