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Abstract

Eukaryotic elongation factor 2 kinase (eEF2K) is a stress-responsive regulator of protein synthesis implicated in melanoma progression, but its role in tumor immune evasion remains poorly defined. We investigated how eEF2K influences programmed death ligand 1 (PD-L1) expression through modulation of Cyclin D1. We analyzed gene expression and dependency datasets from The Cancer Genome Atlas and the Cancer Dependency Map. Protein–protein interactions were assessed by co-immunoprecipitation. Cyclin D1 was inhibited pharmacologically with palbociclib. Immune responses were evaluated in murine B16-OVA and human A2058 melanoma models using flow cytometry and immunohistochemistry after genetic or pharmacologic modulation of eEF2K and Cyclin D1. We discovered that high eEF2K expression correlated with elevated PD-L1 levels and poorer clinical outcomes in patients with melanoma. Mechanistically, eEF2K suppressed Cyclin D1 expression, while loss of eEF2K led to Cyclin D1 upregulation and consequent stabilization of PD-L1 protein. Co-immunoprecipitation confirmed a physical interaction between eEF2K and Cyclin D1. Pharmacologic inhibition of Cyclin D1 reversed PD-L1 accumulation and mitigated eEF2K-driven immune suppression. In vivo, eEF2K inhibition decreased PD-L1 expression and enhanced CD8+ T-cell infiltration and cytotoxicity. Palbociclib treatment similarly restored cytotoxic T lymphocyte function and improved antitumor immunity in eEF2K knockout tumors. Our findings reveal that eEF2K drives immune evasion in melanoma by stabilizing PD-L1 through Cyclin D1 suppression. Targeting the eEF2K–Cyclin D1–PD-L1 axis represents a promising strategy to augment immune checkpoint blockades and improve antitumor immune responses.

Document Type

Article

Publication Date

2026

Notes/Citation Information

© The Author(s) 2025. Published by Oxford University Press on behalf of The American Association of Immunologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

Digital Object Identifier (DOI)

https://doi.org/10.1093/jimmun/vkaf278

Funding Information

This work was supported by National Institutes of Health (grant numbers R01CA282254 to J.-M.Y. and J.S., and R01CA273002 and R21AI167793 to J.S.).

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