Sirt2 Inhibition Enhances Metabolic Fitness and Effector Functions of Tumor-Reactive T Cells

Dysregulated metabolism is a key driver of maladaptive tumor-reactive T lymphocytes within the tumor microenvironment. Actionable targets that rescue the effector activity of antitumor T cells remain elusive. Here, we report that the Sirtuin-2 (Sirt2) NAD+-dependent deacetylase inhibits T cell metabolism and impairs T cell effector functions. Remarkably, upregulation of Sirt2 in human tumor-infiltrating lymphocytes (TILs) negatively correlates with response to TIL therapy in advanced non-small-cell lung cancer. Mechanistically, Sirt2 suppresses T cell metabolism by targeting key enzymes involved in glycolysis, tricarboxylic acid-cycle, fatty acid oxidation, and glutaminolysis. Accordingly, Sirt2-deficient murine T cells exhibit increased glycolysis and oxidative phosphorylation, resulting in enhanced proliferation and effector functions and subsequently exhibiting superior antitumor activity. Importantly, pharmacologic inhibition of Sirt2 endows human TILs with these superior metabolic fitness and effector functions. Our findings unveil Sirt2 as an unexpected actionable target for reprogramming T cell metabolism to augment a broad spectrum of cancer immunotherapies. [Display omitted] •Sirt2, an NAD+-dependent deacetylase, is overexpressed in TILs•Sirt2 interaction with key metabolic enzymes regulates T cell metabolism•Sirt2-deficient T cells exhibit enhanced glycolysis and oxidative phosphorylation•Sirt2 inhibition enhances effector functions of tumor-reactive T cells Hamaidi et al. show that Sirt2 activity governs the metabolic fitness of T cells at the tumor bed by blocking the activity of key metabolic enzymes involved in glycolysis, TCA-cycle, FAO, and glutaminolysis, and thus controls the magnitude of antitumor immune responses.