Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with limited therapeutic options.HCC-induced immunosuppression often leads to ineffectiveness of immuno-promoting therapies.Now suppressing the suppressors has become the potential strategy for cancer immunotherapy.So, figuring out the immunosuppressive mechanisms induced and employed by HCC will be helpful to the design and application of HCC immunotherapy.Here we identified one new subset of human CD14+CTLA-4+ regulatory dendritic cells (DCs) in HCC patients, representing ~13% of PBMCs.CD14+DCs could significantly suppress T cell responses in vitro via IL-10 and IDO.Unexpectedly, CD14+DCs expressed high levels of CTLA-4 and PD-1, and CTLA-4 was found to be essential to IL-10 and IDO production of CD14+DCs.So, we identified a novel human tumor-induced regulatory DC subset, which suppresses anti-tumor immune responses via CTLA-4-dependent IL-10 and IDO production, indicating the important role of non-regulatory T cellderived CTLA-4 in tumor immune escape or immunosuppression.Our data outline one mechanism for HCC to induce systemic immunosuppression by expanding CD14+DCs which may contribute to HCC progression.Thus, our results add new insight to the mechanism for HCC-induced immunosuppression and may also provide a previously unrecognized target of immunotherapy for HCC.