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.

代谢失调是肿瘤微环境中肿瘤反应性 T 淋巴细胞适应不良的关键驱动因素。拯救抗肿瘤 T 细胞效应活性的可行靶点仍然难以捉摸。在此，我们报道 Sirtuin-2 (Sirt2) NAD ⁺依赖性脱乙酰酶抑制 T 细胞代谢并损害 T 细胞效应功能。值得注意的是，人肿瘤浸润淋巴细胞 (TIL) 中 Sirt2 的上调与晚期非小细胞肺癌 TIL 治疗的反应呈负相关。从机制上讲，Sirt2 通过靶向参与糖酵解、三羧酸循环、脂肪酸氧化和谷氨酰胺分解的关键酶来抑制 T 细胞代谢。因此，Sirt2缺陷型小鼠T细胞表现出糖酵解和氧化磷酸化增加，从而增强增殖和效应功能，并随后表现出优异的抗肿瘤活性。重要的是，Sirt2 的药理抑制赋予人类 TIL 优异的代谢适应性和效应功能。我们的研究结果揭示了 Sirt2 是一个意想不到的可操作靶点，用于重编程 T 细胞代谢，以增强广泛的癌症免疫疗法。