Dendritic cell(DC)-based therapies have been introduced to treat cancer. In spite of pre-clinical promise, a response in patients has been disappointing. Immunosuppressive molecules produced by tumor or host cells appear to be at least partially responsible for the poor outcome.Identification and blockade of tumour-derived immunosuppressive molecules are necessary to improve clinical efficacy. This study aims to investigate the role of macrophage inhibitory factor 1 (MIC-1) in DC-mediated immunosuppression in melanoma and determine whether there is an improvement in the outcome of DC-therapy for melanoma when MIC-1 expression is inhibited.Here, we demonstrate that MIC-1 expressed in DCs inhibited DCs maturation and suppressed DC immune function by evidence that MIC-1 transgenic DCs or recombinant humanMIC-1 treated DCs expressed lower levels of costimulatory molecules, signal 3 cytokine IL12 and proinflammatory cytokines IFN-γ, attenuated allogeneic T cell response, and generated more regulatory T cells. In contrast, lack of MIC-1augmented immune responses of DCs. We also demonstrated that MIC-1 utilized TGFβ receptor II and suppressed the NFκB signaling pathway to exert its immune suppressive role. Moreover, administration of MIC-1 deficient DCs reduced tumor growth in melanoma-bearing mice as compared with wild-type of DCs. In conclusion, MIC-1 is a new target for improving an anti-cancer effect of DC-based therapies.