Among human malignancies, primary liver tumors account for 9% of all cancer deaths worldwide and 12% in developing countries. HCC accounts for up to 85% of liver cancers and is one of the leading lethal malignancies worldwide. Chronic liver damage caused by viral infection (HBV and HCV), alcohol, non-alcoholic fatty liver disease (NAFLD)-associated chronic inflammation, fibrosis, cirrhosis, or a combination of these factors increases the risk for HCC. Notably, NAFLD, a hepatic manifestation of metabolic syndrome, affects nearly 25% of the US population, and its incidence is rapidly increasing since obesity and metabolic syndrome are growing epidemics worldwide. Although the risk factors are well defined, HCC is still an aggressive and difficult-to-treat malignant disease with poor outcome and limited therapeutic options. In fact, major obstacles for effective treatment of this cancer is that HCC is frequently resistant to chemotherapy and radiotherapy, and there is a high frequency of tumor recurrence after curative surgical resection. Currently, there is a strong rationale for immune intervention in HCC, but recent clinical trials have demonstrated that the benefits of immunotherapy are relegated to a small fraction (~20%) of cancer patients, including these with HCC. This prompts the need for greater understanding of the mechanisms underlying liver cancer cell plasticity and adaptation, as well as developing novel therapeutic approaches to achieve more effective and selective cure of this disease. Hsf1, as the master activator of the classical heat shock response and guardian of the proteome, has been implicated in the pathogenesis of cancer. We have discovered that genetic inactivation of Hsf1 in pre-clinical mouse cancer models leads to remarkable inhibition of HCC development. On the basis of published and preliminary studies we propose a novel pathogenic mechanism whereby Hsf1 activation promotes HCC development by stimulating both the protein folding capacity of the cell and regulating anabolic metabolic pathways, thus perpetuating chronic hepatic metabolic disease. Our recent research revealed that the Hsf1 transcriptional program enables malignant cells to escape immune surveillance. This may provide a new approach to improve HCC treatment by improving the anti-tumor immune capacity targeting Hsf1 activity. Our experimental strategy entails the following three major approaches: 1. Determine the impact of hsf1 deletion on liver cancer initiation and explore its therapeutic implications for advanced HCC, 2. Determine the metabolic and epigenetic mechanisms by which Hsf1 ablation induces an effective anti-tumor CD8+ T cell response,...