SIRT7 regulates T-cell antitumor immunity through modulation BCAA and fatty acid metabolism

SIRT7, one of the least studied members of the Sirtuins family, is an NAD⁺-dependent lysine deacetylase and desuccinylase. While previous studies using affinity enrichment and quantitative proteomics identified numerous lysine-deacetylated substrates of SIRT7, its lysine-desuccinylated substrates remain underexplored, limiting our understanding of its role in cellular homeostasis. Here, we demonstrated that SIRT7 is predominantly expressed in immune tissues, especially in adaptive immune cells, including T cells. Through proteomics, lysine succinylome, and acetylome analysis of spleen from wild-type (WT) and Sirt7^-/- mice, we identified significant succinylation of proteins involved in the branched-chain amino acid (BCAA) catabolism pathway in Sirt7^-/- mice. We further found that SIRT7 partially localizes to mitochondria, interacting with key enzymes of the BCAA catabolism pathway and promoting their desuccinylation. Sirt7 deficiency leads to enhanced BCAA catabolism, accumulation of acyl-CoA, and increased fatty acid (FA) synthesis. As T cells rely heavily on amino acid metabolism for activation, differentiation, and function, we investigated the impact of SIRT7 using a T cell-specific Sirt7 knockout mouse model (Sirt7^fl/flCd4-Cre). Our results show that SIRT7 is crucial for T cell proliferation, activation, and antitumor function. Sirt7 deficiency in T cells results in the accumulation of BCAA metabolites and FAs, reduced cytotoxic cytokines secretion such as IFN-γ, and T cell exhaustion. Reducing BCAA levels with BT2, a BCKDK inhibitor, or BCAA-free treatment alleviated these effects, while FA treatment exacerbates them. Overall, our findings identify SIRT7 as a critical regulator linking BCAA and FA metabolism to T cell antitumor immunity, providing new insights into its potential as a therapeutic target.