We report interferon-g-like activity of IL27 in tumor cells of different tissue origin when comparing microarray analyses of IFNg (STAT1-dominated response) or IL6-type cytokines (IL6, hyper-IL6 (hy-IL6) or OSM) (STAT3-dominated response) to IL27 responses. Moreover, we do not find an effective STAT3-dependent response nor an induction of a sensitive and STAT3-specific reporter gene construct upon IL27 treatment of cancer cells. Interestingly, the availability of STAT1 seems critical in the shaping of the IL27 response, as the siRNA knock-down of STAT1 revealed the ability of IL27 to induce the acute-phase protein g-fibrinogen, a typical IL6 family characteristic. Interestingly, IL27 and IFNg mediated upregulation of genes associated with increased tumor immune clearance (e.g.TAP2, MHC-I) as well as an upregulation of proteins associated with immune escape, e.g. PD-L1 or IDO-1. Interestingly, we observe differences in the expression of the latter in different HCC cell lines and differences in expression when comparing IL27 and IFNg. The IL2 secretion of PBMCs incubated with IL27 pre-treated cancer cells decreases but this decrease is overcompensated by administration of anti-PD-L1 antibodies, suggesting that the IL27 mediated PD-L1 upregulation induces immune suppression in tumors (which is however effectively prevented by anti-PD-L1 antibodies). Moreover, we describe that the responses to the gp130-engaging cytokine IL27 (but not those to IFNs) can be inhibited by IL6-type cytokine pre-stimulation, likely by a SOCS3-mediated mechanism. Thus, IL27 recapitulates IFNg responses in liver cells with the notable difference of inducing less IDO1 protein expression. IL27 strongly differs from IFNg by its sensitivity to SOCS3 mediated feedback inhibition. This suppression can be antagonized by administration of antibodies against IL6 type cytokines or receptors. Thus the antitumor effects of IL27 might be increased by combining IL27 with blocking antibodies against PD-L1 or/and IL6 type cytokines.