A functional single-cell metabolic survey identifies Elovl1 as a target to enhance CD8+ T cell fitness in solid tumours

• DOI: 10.1038/s42255-025-01233-w
• Publication Date: 2025-03-10T10:04:45Z
• Authors: Samantha Pretto; Qian Yu; Pierre Bourdely; Sarah Trusso Cafa...; Heleen H. Van Acker; Joren Verelst; Elena Richiardone; Lotte Vanheer; Amir Roshanzadeh; Franziska Schnepp...; Charlotte Cresens; Maria Livia Sassano; Jonas Dehairs; Martin Carion; Shehab Ismail; Patrizia Agostinis; Susana Rocha; Tobias Bald; Johan Swinnen; Cyril Corbet; Sophia Y. Lunt; Bernard Thienpont; Mario Di Matteo; Massimiliano Mazzone

Abstract Reprogramming T cell metabolism can improve intratumoural fitness. By performing a CRISPR/Cas9 metabolic survey in CD8 + cells, we identified 83 targets and applied single-cell RNA sequencing to disclose transcriptome changes associated with each perturbation the context of pancreatic cancer. This revealed elongation very long-chain fatty acids protein 1 ( Elovl1 ) as target sustain effector functions memory phenotypes cells. Accordingly, inactivation adoptively transferred cells combined anti-PD-1 showed therapeutic efficacy resistant melanoma tumours. The accumulation saturated -deficient destabilized INSIG1, leading SREBP2 activation, increased plasma membrane cholesterol stronger receptor signalling. mitochondrial fitness acid oxidation, thus withstanding stress imposed by tumour microenvironment. Finally, ELOVL1 correlated response patients melanoma. Altogether, targeting synergizes promote effective responses.