Achieving CD8+ T cell-dependent lethality by targeting cancer USP14 in hepatocellular carcinoma

Abstract The application of immunotherapies in hepatocellular carcinoma (HCC) have been hindered by resistance to therapeutics. Cancer cell-induced CD8 + T cell dysfunction may account for the failure of tumor immunotherapies. Here, we identified USP14 as an essential driver of cancer cells tolerance to CD8 + T cells through genome-wide screening. scRNA-seq showed that cancer USP14 was frequently upregulated in tumor tissues from patients with HCC. The elevated USP14 was positively correlated with resistance to immunotherapy and poor prognoses. Inhibition of cancer USP14 arrested the growth of HCC with the existence of CD8 + T cells in vivo and in vitro. Furtherly, targeting cancer USP14 boosted immunotherapy efficacy. Mechanistically, the USP14 highly-expressed HCC cells were avidly consumed and outcompeted CD8 + T cells for glucose by stabilizing GLUT1 expression, resulting in CD8 + T cells starving and dysfunction. Collectively, our data defined USP14 as a potential immunotherapy target in HCC.