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Updated: Jul 27, 2025

Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology
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Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology

Published on: May 2, 2025

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Elevated nuclear PIGL disrupts the cMyc/BRD4 axis and improves PD-1 blockade therapy by dampening tumor immune

Hua Yu1, Tiezhu Shi1, Linli Yao2

  • 1Precise Genome Engineering Centre, School of Life Sciences, Guangzhou University, Guangzhou, 510006, China.

Cellular & Molecular Immunology
|June 6, 2023
PubMed

Insights

Phosphatidylinositol-glycan biosynthesis class L (PIGL) reprogramming of the tumor microenvironment enhances lenvatinib and PD-1 blockade therapy for hepatocellular carcinoma (HCC). Nuclear PIGL improves patient prognosis and guides treatment decisions.

Area of Science:

  • Oncology
  • Immunology
  • Metabolic Engineering

Background:

  • Hepatocellular carcinoma (HCC) poses a significant challenge, often requiring combination therapies like lenvatinib and programmed death-1 (PD-1) blockade.
  • Improving the efficacy of these treatments necessitates understanding the underlying metabolic and microenvironmental factors that influence response.

Purpose of the Study:

  • To identify suppressive metabolic enzymes that sensitize HCC to lenvatinib and PD-1 blockade therapy.
  • To elucidate the role of phosphatidylinositol-glycan biosynthesis class L (PIGL) in modulating the tumor microenvironment (TME) and therapy response.

Main Methods:

  • CRISPR-Cas9 screening was employed to identify key metabolic enzymes.
  • In vitro and in vivo experiments assessed the impact of PIGL depletion on tumor cells and the TME.
  • Analysis of protein interactions and gene expression, including cMyc/BRD4 and FGFR2-mediated phosphorylation, was performed.
  • Clinical data correlation with PIGL levels and patient outcomes was evaluated.

Main Results:

  • PIGL depletion did not affect tumor cell growth in vitro but reprogrammed the TME in vivo.
  • Nuclear PIGL disrupts cMyc/BRD4 interactions, decreasing immunosuppressive chemokines CCL2 and CCL20.
  • PIGL phosphorylation at Y81 by FGFR2 promotes its cytoplasmic localization, increasing CCL2 and CCL20.
  • Elevated nuclear PIGL correlates with better HCC prognosis and CD8+ T-cell infiltration.

Conclusions:

  • Nuclear PIGL plays a critical role in shaping an anti-tumor TME, enhancing lenvatinib and PD-1 blockade efficacy.
  • PIGL-Y81 phosphorylation status is a key regulator of PIGL's function in the TME.
  • Nuclear PIGL intensity and PIGL-Y81 phosphorylation serve as potential biomarkers for guiding combination therapy in HCC patients.
Keywords:
CCL2/20Nuclear PIGLPD-1 antibodyTumor immune evasion.cMyc

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