Abstract
Sirtuin 1 (SIRT1) and Sirtuin 2 (SIRT2) are NAD⁺-dependent deacetylases that regulate cancer metabolic stress, exerting their effects primarily through post-translational modification of metabolic enzymes and transcription factors. They modulate glucose, lipid, and mitochondrial metabolism, as well as immune metabolism responses within the tumor microenvironment. Depending on cellular context, they can promote or suppress tumor growth by directing energy production, redox balance, and metabolic adaptation. These context-dependent and often opposing activities constitute a Yin-Yang mode of regulation in cancer metabolism, reflecting a dynamic balance between metabolic activation and constraint. Autophagy has emerged as a critical metabolic integration node regulated by both SIRT1 and SIRT2, linking nutrient sensing, mitochondrial quality control, and stress adaptation. This review summarizes recent advances in understanding how SIRT1 and SIRT2 coordinate tumor metabolism and discusses therapeutic strategies that target their regulatory balance to reprogram cancer metabolism. SIRT2 also functions as a metabolic checkpoint that restrains CD8⁺ T cell effector metabolism, providing a rationale for combining SIRT2 inhibition with immune checkpoint blockade in metabolically stressed tumor microenvironments.