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Genetic manipulation of OGT enhances NK cell-mediated cytotoxicity in tumor immunity

Se-Chan Oh1, Bong Chan Jeon2, In-Hwan Jang1

  • 1Center for Gene and Cell Therapy, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea.

Journal of Advanced Research
|September 6, 2025
PubMed
Abstract

Insights

Enhancing O-GlcNAcylation boosts natural killer (NK) cell cancer-killing ability. Genetically modified NK cells with stable O-GlcNAcylation show improved function, overcoming tumor microenvironment challenges for better cancer immunotherapy.

Area of Science:

  • Immunology
  • Cancer Biology
  • Metabolic Regulation

Background:

  • Natural killer (NK) cells are crucial for immune surveillance and cancer immunotherapy.
  • NK cell function is often impaired by the tumor microenvironment (TME).
  • O-GlcNAcylation's role in NK cell function and cancer therapy is not well understood.

Purpose of the Study:

  • To investigate the impact of O-GlcNAcylation on NK cell cytotoxicity.
  • To explore O-GlcNAcylation as a therapeutic target for enhancing anti-tumor immunity.
  • To assess the potential of modulating O-GlcNAcylation for cancer immunotherapy.

Main Methods:

  • Investigated O-GlcNAcylation's effect on NK cell cytotoxicity under cytokine stimulation and pharmacological modulation.
  • Utilized mass spectrometry to identify O-GlcNAc-modified proteins in NK cells.
  • Genetically engineered NK92 cells to ensure stable O-GlcNAcylation by deleting the OGT-ISS region.
  • Evaluated NK cell function in TME-mimicking conditions and in vivo tumor models.
  • Performed whole-transcriptome analysis to understand molecular mechanisms.

Main Results:

  • Increased O-GlcNAcylation via cytokine stimulation or OGA inhibitor enhanced NK cell cytotoxicity.
  • Proteomic analysis identified key O-GlcNAc-modified proteins, including NK cell regulators and LRPPRC.
  • Genetically engineered NK92 cells with stable O-GlcNAcylation maintained potent cytotoxicity in TME conditions and showed superior in vivo tumor killing.
  • Gene expression analysis revealed altered TGF-β and Type I interferon signaling, alongside changes in cell adhesion and mobility genes.

Conclusions:

  • Stabilizing and enhancing O-GlcNAcylation improves NK cell's cancer-killing capacity and overcomes TME suppression.
  • Genetic engineering of O-GlcNAc pathways offers a potent strategy to augment NK-based cancer immunotherapies.
  • Targeting O-GlcNAcylation presents a promising avenue for developing more effective cancer treatments.
Keywords:
Cancer immunotherapyCytotoxicityNK cellO-GlcNAcylationOGT-ISS deletion

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