Aggravated inflammation is often associated with metabolic disturbances that contribute to cancer initiation. Further, overt immunosuppression support cancer progression with accumulation of proinflammatory cytokines, and infiltration of immunosuppressive cells. Therefore, combinatorial targeting of both inflammation and immunosuppression pathways may improve cancer immunotherapy. Herein, we examined immune response, metabolic imbalance affecting fat and lean tissue in vivo in B16F10 tumor-bearing mice. Moreover, we investigated mono- or multimodal- immunotherapies that target both production of inflammatory cytokines and myeloid-derived suppressor cells (MDSCs) in order to augment tumor regression. To this end a group (n=12) of either B16F10-bearing mouse receiving dexamethasone (DEX), or (n=12) depleting monoclonal antibodies (mAbs) anti-Gr1 (RB6-8C5), both (n=12) DEX and anti-Gr1, or (n=12) vehicle were tested. First, we observed that polymorphonuclear (PMN)-MDSCs (Ly6G+) and monocytic (M)-MDSCs (Ly6C+) found within the spleen of B16F10-bearing mice express interleukin (IL)-10, whilst inflammatory cytokine tumor necrosis factor (TNF)-α is increased in peripheral blood. Notably, MDSC (Gr1+CD11b+) expansion and function found in the spleen of B16F10-bearing mice were markedly reduced following dexamethasone (DEX) treatment, though number of Gr1+CD11b+ cells in bone marrow were not significantly affected. DEX lowered plasma TNF-α and IL-10 levels, as well as levels of intracellular IL-10 expressed by Gr1+CD11b+ MDSCs in B16F10-bearing mice. Significantly, a combined immunotherapy associating both DEX and depletion of MDSCs has considerably reduced inflammation as measured by C-reactive protein (CRP), serum amyloid A (SAA), and TNF-α in circulating blood of B16F10-bearing mice, compared to control mice receiving DEX or anti-Gr1 mAbs alone. Moreover, melanoma regression measured in tumor size and lung metastasis, as well as constraint of white adipose and lean tissue wasting were noticeable compared to mice receiving treatment with DEX, or anti-Gr1 mAbs alone. Our results suggest that combinatorial targeting of depletion of MDSC (mAbs) and inflammation (DEX) in immunotherapy may facilitate tumor regression.