Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths and develops as a result of chronic liver injury and inflammation. The major causes of chronic liver injury are hepatitis B and C virus infections, but in the US and Europe their pathogenic importance has been eclipsed by non-alcoholic (NASH) and alcoholic (ASH) steatohepatitis. Using a novel mouse model developed in our lab, we have shown that NASH pathogenesis and HCC development depend on endoplasmic reticulum (ER) stress, elevated de novo lipogenesis, ballooning degeneration of hepatocytes, induction of TNF expression and hepatic accumulation of p62. NASH and ASH are also associated with upregulation of immunoglobulin A (IgA), first identified in human patients and confirmed in our mouse model. We found that in both human and mouse livers, elevation of circulating IgA is due to accumulation of IgA-producing plasmablasts and plasma cells. These IgA-producing cells express high amounts of PD-ligand 1 (PD-L1) and IL-10 and possess the ability to inhibit activation of HCC-directed cytotoxic CD8+ T lymphocytes (CTL). The inhibition of CTL activation prevents liver protective immunosurveillance, thereby resulting in growth and malignant progression of neoplastic nodules that develop as a result of chronic liver inflammation. Importantly, depletion or ablation of liver IgA-producing cells results in re-invigoration of HCC-directed CTLs, thereby leading to tumor regression. Thus, treatments that inhibit accumulation of liver IgA-producing cells should be effective in preventing progression from NASH and ASH to HCC and inducing regression of established tumors.