Hepatocellular carcinoma (HCC) remains a public health challenge that requires dedication to develop new treatment options due to its high recurrence rate and poor prognosis. Interferon-producing killer dendritic cell (IKDC) is a subset of INF-gamma secreting immune cells that modulates acquired immunity and possesses cytolytic ability. We modified IKDC isolated from the murine spleen with T-bet lentiviral transduction to enhance its cytotoxicity against HCC, and acquired IKDC overexpressing T-bet (T-bet-IKDC) for the first time. T-bet-IKDC has increased INF-gamma secretion and surface expression of NKG2D and TRAIL. In vitro study by MTS assay and flow cytometry showed enhanced anti-tumor effect against H22 cells via apoptosis induction in a dose- and time-dependent manner. In vivo study on H22-bearing mice confirmed increased INF-gamma secretion, reduced tumor size, increased caspase 3 cleavage, and upregulation of cytotoxic molecules after T-bet-IKDC administration. The study suggested prospective application of T-bet-IKDC in future immunotherapy for HCC treatment. (C) 2020 Elsevier Inc. All rights reserved.