# GNPAT promotes immunosuppression in hepatocellular carcinoma by activating the plasmalogen-PPARγ pathway to drive M2 macrophage polarization

## TL;DR

This study shows that GNPAT promotes liver cancer growth by creating an immunosuppressive environment through a specific metabolic pathway involving plasmalogens and PPARγ.

## Contribution

The novel finding is that GNPAT drives immunosuppression in HCC via the plasmalogen-PPARγ pathway and M2 macrophage polarization.

## Key findings

- GNPAT is highly expressed in HCC and linked to poor outcomes and immunosuppressive infiltration.
- GNPAT promotes HCC cell proliferation and resistance to apoptosis via plasmalogen synthesis and PPAR activation.
- GNPAT overexpression polarizes macrophages to M2-like phenotype, enhancing immunosuppressive tumor microenvironment.

## Abstract

Hepatocellular carcinoma (HCC) is a major threat to human health worldwide. Its suboptimal responses to current therapies are largely attributable to the immunosuppressive tumor microenvironment (TME) that dampens the efficiency of available treatments. Although metabolic reprogramming is regarded as a hallmark of HCC, the exact role of peroxisomal metabolism in immune evasion is poorly understood. By integrating bioinformatic analysis of TCGA-LIHC datasets and peroxisomal gene profiling, glyceronephosphate O-acyltransferase (GNPAT) was identified as a regulator of HCC pathogenesis. GNPAT was highly expressed in malignant tissues and positively associated with poor clinical outcomes and immunosuppressive cellular infiltration types. Functional experiments showed that GNPAT facilitated the proliferation, migration, and resistance to apoptosis of HCC cells in an autocrine manner via enhancing plasmalogen synthesis and downstream PPAR pathway activation. Interestingly, overexpression of GNPAT in HCC cells polarized macrophages to the M2-like phenotype and reinforced immunosuppressive TME through the plasmalogen-PPAR axis. An unrecognized mode of immunometabolic crosstalk mediated by peroxisomal metabolism in HCC was thereby revealed, providing a preclinical rationale and mechanistic basis for future exploration of GNPAT inhibition as a potential therapeutic strategy to antagonize immunosuppression and enhance antitumor immunity.

Schematic diagram illustrating that GNPAT promotes HCC progression and remodeling of the immune microenvironment through the regulation of the plasmalogen–PPARγ axis. Graphical Abstract was created by biorender and licensed to be published.Diagram illustrating the role of GNPAT in phospholipid biosynthesis and immune cell infiltration. Bioinformatics analysis identifies GNPAT's function in the peroxisome pathway using patient serum. The lower section details enzymatic reactions in peroxisomes and the endoplasmic reticulum, leading to the formation of plasmalogens and activation of PPARγ, contributing to malignant progression. Visual elements include fatty acyl-CoA conversion, cellular and molecular structures, and progression from M0 to M2 cells.

Schematic diagram illustrating that GNPAT promotes HCC progression and remodeling of the immune microenvironment through the regulation of the plasmalogen–PPARγ axis. Graphical Abstract was created by biorender and licensed to be published.