Tumor microenvironment-associated oxidative stress impairs SIRT1 secretion to suppress anti-tumor immune response.

Abstract

Sirtuin-1 (SIRT1) is a classical histone deacetylase well known for its roles in intracellular pathways such as energy metabolism, DNA damage response, and genome stability maintenance. We report that SIRT1 can be secreted into the tumor microenvironment (TME) through an unconventional protein secretion pathway, effectively inhibiting tumor growth. However, under the stressful conditions of the TME, SIRT1 undergoes increased methylation, which impedes its secretion. Consequently, tumor-infiltrating M2 macrophages are unable to acquire sufficient SIRT1 from the TME, resulting in a significant decrease in SIRT1 levels within these cells. This SIRT1 decline leads to elevated expression of programmed cell death ligand 1 (PD-L1) on M2 macrophages, which in turn contributes to CD8⁺ T cell exhaustion through the programmed cell death protein 1/PD-L1 interaction pathway. These findings unveil the multifaceted roles and regulatory mechanisms of SIRT1 within the complex TME, providing deeper insights that significantly enhance our understanding of tumor immune-evasion strategies.