PROJECT SUMMARY Liver cancer ranks fifth in frequency and third in mortality, with estimated numbers of over 700,000 new cases every year worldwide. Hepatocellular carcinoma (HCC) is the most common form of liver cancer that originates from viral infection (e.g., hepatitis B, C) or injury-driven chronic inflammation (e.g., cirrhosis from excessive alcohol consumption or obesity-induced steatohepatitis) in the liver. Although HBV and HCV incidence are on the decline, the obesity epidemic has resulted in an increase in the number of new cases of HCC in developed countries including the US. Thus, identifying targetable mediators of HCC represents an important unmet medical need. Interleukin (IL)-27 is a cytokine that plays immunomodulatory roles in infection and autoimmunity. IL27R signaling reduces inflammation in infectious and inflammatory models ostensibly by suppressing a pro- inflammatory immune response. These findings led us to speculate that IL27 might function similarly to limit liver inflammation and halt HCC development. Surprisingly, however, we have discovered that eliminating IL27R signaling suppresses tumor development in two in vivo mouse models of HCC which was accompanied by the increased accumulation and activation of innate and adaptive cytotoxic immune cells, suggesting a new, pro- tumorigenic role for this otherwise anti-inflammatory cytokine. Here we propose to investigate cellular and molecular mechanisms of how IL27R signaling suppresses anti-cancer cytotoxic immune response using highly relevant to human HCC MUP-uPA mouse model combined with cell type specific ablation of IL27R and integrated array of cutting-edge transcriptomics, histological, immunological, and molecular biology analyses. Finally, we will test the efficacy and identify cellular and molecular mechanisms of IL27 signaling blockade either alone or in combination with other immunotherapies, as a new therapeutic avenue for HCC. Overall, the proposed research will uncover the role of IL27R signaling in HCC development and determine the beneficial mechanisms of its blockade. This work has strong translational potential with game- changing ramifications for HCC.