Background <p>Many studies have reported increased Sirt6 expression and activity in many tumor tissues, and the expression level is inversely linked to overall patient survival. This study explored how Sirt6 affects tumor growth and immune surveillance.</p> Methods <p>UBCS039, a selective Sirt6 activator, was dissolved in dimethyl sulfoxide (DMSO) and intraperitoneally administered to BALB/c-nude mice. These mice were then given injections of human tumor-derived HeLa, MB-231, Lm-3, or Hcc827 cells to establish a tumor-bearing model by routine methods.</p> Results <p>Compared with tumor-bearing mice pretreated with DMSO or PBS, the mice pretreated with UBCS039 showed larger tumors. The levels of granulocyte–macrophage colony-stimulating factor (GM-CSF), IL-10, adenosine (ADO) and NK cells were elevated in the peripheral blood of UBCS039-pretreated mice, and the IFN-γ level was decreased. Increased expression levels of Sirt6, PD-L1, NF-κB, and PD-1 were detected in the tumor tissues of UBCS039-pretreated mice. A greater abundance of M2 macrophages, also termed tumor-associated macrophages (TAMs), was observed in UBCS039-pretreated mouse tumors. Moreover, upregulation of novel Lao1 (interleukin 4-induced 1, IL4I1), which is known to control M2 polarization, was specifically detected in tumor tissues from UBCS039-treated mice via transcriptomic analysis and was verified by real-time PCR and western blotting. UBCS039 also stimulated M0-type and M1-type macrophage polarization to the M2-type phenotype in vitro, and Sirt6 and Lao1 expression increased during this process.</p> Conclusions <p>Sirt6 can increase ADO, PD-L1 and PD-1 levels; decrease IFN-γ levels; and promote M2 polarization through the upregulation of Lao1 expression, which increases tumor growth by suppressing immune surveillance.</p>