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Cullin-5 RING E3 ligase limits CD8⁺ T-cell persistence and effector responses during chronic antigen stimulation

Year: 2026
Type: article
Abstract: T-cell exhaustion limits durable antitumor responses and remains a barrier to adoptive cell therapies (ACT) in solid tumors. To identify regulators of T-cell persistence, we performed genome-wide CRISPR knockout screens in primary human CD8⁺ T cells expressing an NY-ESO-1-specific T-cell receptor and subjected them to repeated tumor cell rechallenge. These screens revealed enrichment of single-guide RNAs targeting components of Cullin-RING E3 ligases, particularly Cullin-5 (CRL5) assemblies comprising CUL5, RNF7, and ARIH2. Disruption of CRL5 genes in T cells preserved cytotoxic activity and enhanced cytokine production while sustaining effector-associated transcriptional programs and suppressing exhaustion-related signatures. Pharmacologic inhibition of cullin neddylation with the NEDD8-activating enzyme inhibitor MLN4924 recapitulated CRL5 loss and enhanced T-cell effector function in vitro. In a human melanoma xenograft model, ACT with CRL5-deficient T cells improved tumor control. Together, these findings identify CRL5 as a negative regulator of T-cell fitness and a potential therapeutic target to enhance ACT durability in solid tumors.
DOI: 10.1158/2326-6066.cir-26-0181
Authors: Justin D. Saco, Daniel Karin, J.J. Patten, Stefanie Bachl, Carter Ching, Nupura Kale, Yichen Fan, Egmidio Medina, Nataly Naser Al Deen, Ameya Champhekar, William G. Kaelin, Brenda A. Schulman, Katie M. Campbell, Julia Carnevale, Cristina Puig-Saus, Antoni Ribas
Institutions: University of California, Los Angeles, Gladstone Institutes, University of California, San Francisco, University of San Francisco, Dana-Farber Cancer Institute, Max Planck Institute of Biochemistry
Language: English
Subfield: Immunology
Open Access status: hybrid
OpenAlex ID: W7221890219
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