Among numerous gene therapeutic strategies for cancer treatment, gene transfer by conditionally replicative adenovirus (CRAd) of interferon-gamma (IFN-gamma) may be useful because of the possibility that it will yield IFN-gamma-mediated antiangiogenesis, immune responses, and CRAd-mediated oncolysis. In this study, we constructed a human TERT promoter-mediated oncolytic adenovirus targeting telomerase-positive cancers and armed with a mouse or human IFN-gamma gene to generate novel immune gene-viral therapeutic systems, CNHK300-mIFN-gamma and CNHK300-hIFN-gamma, respectively. The systems can specifically target, replicate in, and lyse cancer cells, while sparing normal cells. The advantage of these systems is that the number of transgene copies and their expression increase markedly via viral replication within infected cancer cells, and replicated viral progeny can then infect additional cancer cells within the tumor mass. CNHK300-mIFN-gamma induced regression of xenografts in liver cancer models in both immunodeficient and immunocompetent mice by triplex mechanisms including selective oncolysis, antiangiogenesis, and immune responses. We conclude that combining immune gene therapy and oncolytic virotherapy can enhance antitumor efficacy as a result of synergism between CRAd oncolysis and transgene composite antitumor responses.