Underlying dysregulation of the immune system restricts treatment of cancer patients with chronic autoimmune disorders (ADs), especially for relapsing-remitting ADs such as systemic lupus erythematous (SLE). Here, we used our mouse model of chronic IFNg expression (ARE-del) featuring IFNg-associated SLE-like autoimmunity to demonstrate that IL-27 modifies the impact of IFNg over immunity in B16F10-bearing mice. We found that moderate (< 20 pg/ml) but not high levels of IFNg and IL-27 correlate with increased (p=0.02) overall survival and decreased tumor growth rate (p = 0.0154) in B16F10-bearing heterozygous (HET) ARE-del mice compared to wild-type (WT) mice. Examination of lung and subcutaneous grafts revealed that in homozygous (KO) mice exhibit high IFNg and IL-27 levels (p < 0.05), high grade of necrosis (KO > HET > WT), low CD31+ areas (p=0.0463), and multiple MHCII+ tumor-associated macrophages (TAMS). Combined FACS and ELISA data confirmed significant increases in prostaglandin E2 (PGE2) and IL-27 producing MHC II+ CD11b+ F480+ Ly6C high (ly6Chi) monocytes (p=0.002) in ARE-del HET and KO mice. Noticeably, the IL27 receptor was expressed in IFNg-primed TAMS (p< 0.05) but not in B16F10 cells. As high PGE2 levels also characterized grafts, these data support the model that IFNg-primed TAMS are a constant source of PGE2 and IL-27 in B16F10-bearing mice. To substantiate the importance of the IFNg-primed status of macrophages over tumor progression, we examined in vitro invasion testing using 2D (transwell chambers) and 3D (Matrigel) co-culturing protocols of B16F10 and HcMel1274 melanoma cells and IFNg-primed macrophages. IFNg-primed macrophages decreased significantly the speed and invasion abilities of melanoma cells suggesting IFNg-primed macrophages restrain metastatic spread of melanoma cells, but promote immunosuppression via PGE2 and IL-27. Together, our data suggest that IL-27 may modulate immune outcome behind excessive activation of IFNg, a role impacting immunotherapy in tumor-bearing hosts with SLE and other ADs.