Palmitate suppresses CD8+ T cell antitumoral response by disrupting mitochondrial metabolism [ATAC-seq]

Accumulation of lipids in the tumor microenvironment (TME) is a feature of several solid tumors and increased palmitate (PA) availability fosters tumor progression and metastases. The intrinsic effects of PA on cancer cells are well understood, but its role in modulating CD8+ T cells (CTL) functional performances remains elusive. Here, we found that PA alters the mitochondrial metabolism of CTL and prevents their effector functions in an irreversible manner, resulting in impaired antitumoral immunity. Mechanistically, PA-induced mitochondrial blocking demotes histone acetylation and chromatin accessibility and decreases the transcription of genes promoting DNA replication and production of effector molecule production. We identified the metabolic enzyme Sphingosine Kinase 2 (SPHK2) as a molecular target of PA in establishing CTL dysfunction. Consistently, pharmacological inhibition of SPHK2 restored CTL mitochondrial fitness, effector functions and anti-tumor potential. Thus, we reveal that PA fosters tumor progression by impairing CTL antitumor immunity and highlight the therapeutic potential of inhibiting SPHK2 activity to optimize T cellfunctionality.