A functional single-cell metabolic survey identifies Elovl1 as a target to enhance CD8+ T cell fitness in solid tumours
(2025) Nature Metabolism — Vol. 7, n° 3, p. 508-530 (2025)
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- Authors
Bourdely, Pierre 
Mazzone, Massimiliano
- Abstract
- Reprogramming T cell metabolism can improve intratumoural fitness. By performing a CRISPR/Cas9 metabolic survey in CD8+ T cells, we identified 83 targets and we applied single-cell RNA sequencing to disclose transcriptome changes associated with each metabolic perturbation in the context of pancreatic cancer. This revealed elongation of very long-chain fatty acids protein 1 (Elovl1) as a metabolic target to sustain effector functions and memory phenotypes in CD8+ T cells. Accordingly, Elovl1 inactivation in adoptively transferred T cells combined with anti-PD-1 showed therapeutic efficacy in resistant pancreatic and melanoma tumours. The accumulation of saturated long-chain fatty acids in Elovl1-deficient T cells destabilized INSIG1, leading to SREBP2 activation, increased plasma membrane cholesterol and stronger T cell receptor signalling. Elovl1-deficient T cells increased mitochondrial fitness and fatty acid oxidation, thus withstanding the metabolic stress imposed by the tumour microenvironment. Finally, ELOVL1 in CD8+ T cells correlated with anti-PD-1 response in patients with melanoma. Altogether, Elovl1 targeting synergizes with anti-PD-1 to promote effective T cell responses.
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Pretto, S., Yu, Q., Bourdely, P., Trusso Cafarello, S., Van Acker, H. H., Verelst, J., Richiardone, E., Vanheer, L., Roshanzadeh, A., Schneppenheim, F., Cresens, C., Sassano, M. L., Dehairs, J., Carion, M., Ismail, S., Agostinis, P., Rocha, S., Bald, T., Swinnen, J., et al. (2025). A functional single-cell metabolic survey identifies Elovl1 as a target to enhance CD8+ T cell fitness in solid tumours. Nature Metabolism, 7(3), 508-530. https://doi.org/10.1038/s42255-025-01233-w (Original work published 2025)