Abstract
To improve the efficacy of lenvatinib in combination with programmed death-1 (PD-1) blockade therapy for hepatocellular carcinoma (HCC), we screened the suppressive metabolic enzymes that sensitize HCC to lenvatinib and PD-1 blockade, thus impeding HCC progression. After analysis of the CRISPR‒Cas9 screen, phosphatidylinositol-glycan biosynthesis class L (PIGL) ranked first in the positive selection list. PIGL depletion had no effect on tumor cell growth in vitro but reprogrammed the tumor microenvironment (TME) in vivo to support tumor cell survival. Specifically, nuclear PIGL disrupted the interaction between cMyc/BRD4 on the distant promoter of target genes and thus decreased the expression of CCL2 and CCL20, which are involved in shaping the immunosuppressive TME by recruiting macrophages and regulatory T cells. PIGL phosphorylation at Y81 by FGFR2 abolished the interaction of PIGL with importin α/β1, thus retaining PIGL in the cytosol and facilitating tumor evasion by releasing CCL2 and CCL20. Clinically, elevated nuclear PIGL predicts a better prognosis for HCC patients and presents a positive correlation with CD8 + T-cell enrichment in tumors. Clinically, our findings highlight that the nuclear PIGL intensity or the change in PIGL-Y81 phosphorylation should be used as a biomarker to guide lenvatinib with PD-1 blockade therapy.