Metabolic inhibition induces pyroptosis in uveal melanoma
Abstract
Few treatment options are available for patients with metastatic uveal melanoma. Although the bispecific tebentafusp is FDA approved, immunotherapy has largely failed, likely given the poorly immunogenic nature of uveal melanoma. Treatment options that improve the recognition of uveal melanoma by the immune system may be key to reducing disease burden. We investigated whether uveal melanoma has the ability to undergo pyroptosis, a form of immunogenic cell death. Publicly available patient data and cell line analysis showed that uveal melanoma expressed the machinery needed for pyroptosis, including gasdermins D and E (GSDMD and E), caspases 1, 3, 4, and 8, and ninjurin-1. We induced cleavage of GSDMs in uveal melanoma cell lines treated with metabolic inhibitors. In particular, the carnitine palmitoyltransferase 1 (CPT1) inhibitor, etomoxir, induced propidium iodide uptake, caspase 3 cleavage, and the release of HMGB1 and IL-1β, indicating that the observed cleavage of GSDMs led to pyroptosis. Importantly, a gene signature reflecting CPT1A activity correlated with poor prognosis in patients with uveal melanoma and knockdown of CPT1A also induced pyroptosis. Etomoxir-induced pyroptosis was dependent on GSDME but not on GSDMD, and a pyroptosis gene signature correlated with immune infiltration and improved response to immune checkpoint blockade in a set of patients with uveal melanoma. Together, these data show that metabolic inhibitors can induce pyroptosis in uveal melanoma cell lines, potentially offering an approach to enhance inflammation-mediated immune targeting in patients with metastatic uveal melanoma.
RAS ID
78844
Document Type
Journal Article
Date of Publication
4-1-2025
Volume
23
Issue
4
Funding Information
Department of Defense Team Science Award (NIH/NCI R01 CA253977, NCI R01 CA256945) / A Cure In Sight / Thomas Jefferson University Melanoma Research Institute of Excellence Pilot Award / NIH/NCI Cancer Center Support Grant (P30 CA056036)
PubMed ID
39670827
School
Centre for Precision Health / School of Medical and Health Sciences
Copyright
subscription content
Publisher
American Association for Cancer Research
Identifier
Vivian Chua: https://orcid.org/0000-0002-1873-6820
Comments
Varney, S. D., Erkes, D. A., Mersky, G. L., Mustafa, M. U., Chua, V., Chervoneva, I., ... & Aplin, A. E. (2025). Metabolic inhibition induces pyroptosis in uveal melanoma. Molecular Cancer Research, 23(4), 350-362. https://doi.org/10.1158/1541-7786.MCR-24-0508