Gangliosides shed by tumors into their microenvironment (TME) are immunoinhibitory. Interferon-γ (IFN-γ) may boost antitumor immune responses. Thus we wondered whether IFN-γ would counteract tumor ganglioside-mediated immune suppression. To test this hypothesis, we exposed human monocyte-derived LPS-activated dendritic cells (DC) to IFN-γ and to a highly purified ganglioside, GD1a. DC ganglioside exposure decreased TLR-dependent p38 signaling, explaining the previously observed ganglioside-induced down-modulation of pro-inflammatory surface markers and cytokines. Strikingly, while increasing LPS-dependent DC responses, IFN-γ unexpectedly did not counteract the inhibitory effects of GD1a. Rather, induction of indoleamine 2,3-dioxygenase (IDO1), and expression of STAT1/IRF-1 and programmed cell death ligand (PD-L1), indicated that the immunoinhibitory, not an immune stimulatory, IFN-γ-signaling axis, was active. The combination, IFN-γ and DC ganglioside enrichment, markedly impaired DC stimulatory potential of CD8 T-cells. We suggest that gangliosides and IFN-γ may act in concert as immunosuppressive mediators in the TME, possibly promoting tumor progression.