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Generation of Orthotopic Pancreatic Tumors and Ex vivo Characterization of Tumor-Infiltrating T Cell Cytotoxicity
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Published on: December 7, 2019

GPAT4 regulates antitumor immune response through activating the mtDNA-cGAS axis in cancer cells

Zi-Lun Ruan1, Wei Liang1, Yu-Tong Gong1

  • 1Department of Infectious Diseases, Medical Research Institute, Zhongnan Hospital of Wuhan University, Frontier Science Center for Immunology and Metabolism, State Key Laboratory of Virology and Biosafety, Wuhan University, Wuhan, 430071, Hubei, China.

Cell Insight
|July 28, 2026
PubMed

Insights

Targeting Glycerol-3-phosphate acyltransferase 4 (GPAT4) in tumor cells activates innate immune pathways. This enhances anti-tumor responses by increasing immune cell infiltration and improving prognosis in cancers like pancreatic and breast cancer.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Activating tumor-intrinsic innate immunity enhances anti-tumor responses and overcomes resistance to immune checkpoint blockade (ICB).
  • Specific molecular targets for activating these pathways remain insufficiently defined.
  • Glycerol-3-phosphate acyltransferase 4 (GPAT4) is highly expressed in tumors and linked to poor prognosis.

Purpose of the Study:

  • To investigate the role of GPAT4 in tumor immunity.
  • To identify GPAT4 as a potential target for cancer immunotherapy.

Main Methods:

  • Bioinformatic analysis of GPAT4 expression in various cancers.
  • Syngeneic tumor-bearing mouse experiments (C57BL/6J and BALB/c) with GPAT4-deficient tumors.
  • Mechanistic studies involving mitochondrial stress and cGAS pathway activation.
  • Single-cell RNA sequencing of breast and pancreatic tumors.

Main Results:

  • GPAT4 deficiency significantly slowed tumor growth in pancreatic and breast cancer models.
  • GPAT4-deficient tumors showed increased CD8+ T cell infiltration and effector function.
  • GPAT4 deficiency induced mitochondrial stress and activated the cGAS-STING pathway via released mitochondrial DNA (mtDNA).
  • Low GPAT4 expression correlated with enhanced interferon response and infiltration of CD8+ T and NK cells.

Conclusions:

  • GPAT4 acts as a critical innate immune checkpoint molecule within tumor cells.
  • Targeting GPAT4 can activate intrinsic tumor immunity, enhancing anti-tumor immune responses.
  • GPAT4 inhibition represents a promising strategy for improving cancer immunotherapy outcomes.
Keywords:
Antitumor immunityBioinformaticsGPAT4Mitochondrial DNAcGAS-mediated innate immunity

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