Lipid accumulation in the tumor microenvironment is a hallmark of solid tumors, with increased palmitate (PA) availability fostering tumor progression. Although PA’s direct effects on cancer cells are well described, its impact on CD8 T cells cytotoxic T lymphocytes (CTLs) remains unclear. Here, we show that PA irreversibly impairs CTL mitochondrial metabolism, leading to the loss of effector functions and compromised antitumor immunity. PA-induced mitochondrial dysfunction reduced histone acetylation and chromatin accessibility, suppressing transcription of genes involved in T cell replication and effector programs. We identified sphingosine kinase 2 (SPHK2) as a key mediator of PA-induced dysfunction, with pharmacological inhibition of SPHK2 restoring mitochondrial fitness, rescuing CTL effector function, and promoting antitumor activity. These findings uncover a distinct mechanism by which PA drives immune evasion in tumors and highlight SPHK2 as a potential therapeutic target to enhance T cell–based immunotherapies.
Tiberti et al. (Fri,) studied this question.