SIRT4 and neoplasm: In summary, this integrated model positions SIRT1/SIRT6/SIRT5 as an immune-suppressive sirtuin axis that drives Treg expansion, PD-L1 expression, adenosine accumulation, macrophage skewing, and CD8+ exclusion, while SIRT2/SIRT4 constitute an immune-activating axis that sustains effector CD8+ differentiation, cytotoxic infiltration, and maintenance of anti-tumor immunity (Figure 5, Table 5).