GNPAT Promotes Immunosuppression in Hepatocellular Carcinoma by Activating the Plasmalogen-PPARγ Pathway to Drive M2 Macrophage Polarization

Meng Hu^1,2Nan Zhang^1,3Yanqi Wa^1,4Xiao-Ming Wang^1,5Yun Shi¹Min Yao¹Lian-Guo Hou¹Lingling Jiang^1*

• ¹Ministry of Education Key Laboratory of Neural and Vascular Biology, Department of Biochemistry and Molecular Biology, Hebei Medical University, shijiangzhuang, China
• ²Department of Complex Preparation, Shijiazhuang No. 4 Pharmaceutical, Shijiazhuang, China
• ³Hebei University of Chinese Medicine, Shijiazhuang, China
• ⁴Hebei University of Chinese Medicine Hebei Provincial Hospital of Traditional Chinese Medicine, Shijiazhuang, China
• ⁵Department of Clinical Laboratory, The First Hospital of Tsinghua University, Beijing, China

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.