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Background Immune checkpoint inhibitors have shown clinical activity in multiple cancers, yet only some patients are responsive. In some non-responsive tumors, the T lymphocytes can be localized at the tumor margin or can be absent all together. Recent work has suggested that poor T cell infiltration and activation is associated with immunosuppressive tumor-associated macrophages (TAMs). GPNMB is a glycosylated type I transmembrane protein shown to be expressed in multiple cancers. Human melanoma single-cell RNA-seq data showed GPNMB to be upregulated in the myeloid compartment of non-responders. Several cancer mouse models found GPNMB to be expressed in an anti-inflammatory, highly differentiated subtype of TAMs.Methods We used a knockout (KO) GPNMB mouse model to study the effect of this gene on tumor progression in the B16.SIY tumor system. Flow cytometry and single-cell RNA-seq were used to characterize the immune compartment. Monoclonal antibodies were used to deplete immune cells.Results Knockout of GPNMB in the host, but not in tumor cells, led to markedly reduced B16 melanoma growth. Endpoint tumors in KO hosts had more CD8 + T cells, NKT cells, and pro-inflammatory MHC-IIhigh CD86+ macrophages. CD8+ T cell depletion or blocking IFN-γ in vivo eliminated the difference in macrophages, and anti-Thy1 depletion of all T cells led to complete loss of tumor control. Single-cell RNA-seq data revealed no significant differences at baseline between WT and KO mice in immune cells isolated from bone marrow, spleen, and lymph nodes, suggesting GPNMB deficiency did not disrupt normal tissue function. However, it showed significant differences in immune cells isolated from tumors. Relative to WT, KO mice had expanded subpopulations of pro-inflammatory macrophages expressing IFN-induced genes, and relatively smaller subpopulations of other macrophages, characterized by expression of either mitochondrial genes involved in oxidative phosphorylation or of lipid metabolism genes. Macrophages isolated from tumors of KO mice showed decreased suppression of CD8+ T cells in an in vitro co-culture assay. Bone-marrow derived macrophages (BMDMs) polarized towards an anti-inflammatory phenotype upregulated GPNMB expression in vitro. Consistent with STAT binding sites in the GPNMB gene, GPNMB expression was also significantly reduced in STAT6 KO BMDMs.Conclusions Deletion of GPNMB in the host led to improved tumor control and survival in a mouse melanoma model. This effect was mediated through a shift in macrophages towards a non-suppressive phenotype, which may involve modulation of macrophage metabolism. Targeting GPNMB is an attractive consideration to promote improved immune-mediated tumor control through macrophage modulation.Ethics Approval This study obtained ethics approval by the Institutional Animal Care and Use Committee (IACUC) at the University of Chicago as outlined in the animal protocol #71621.