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Enhancement of NK cell activity via DNA-sensing inhibition by Poxin transgene

Ling-Zu Kong1, Seok-Min Kim2, Soo Yun Lee2

  • 1Center for Gene and Cell Therapy, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea; Department of Biochemistry, College of Natural Sciences, Chungnam National University, Daejeon 34134, Republic of Korea.

Journal of Advanced Research
|June 2, 2025
PubMed
Abstract

Insights

Poxin protein inhibits cyclic GMP-AMP synthase (cGAS) DNA sensing in Natural Killer (NK) cells, boosting their cancer-fighting ability. This enhances NK cell-mediated anti-tumor activity and cytotoxicity for improved cancer therapy.

Area of Science:

  • Immunology
  • Cancer Biology
  • Molecular Biology

Background:

  • Natural Killer (NK) cell therapy shows promise for cancer treatment but faces limitations due to short NK cell lifespan and tumor microenvironment suppression.
  • The cyclic GMP-AMP synthase (cGAS) pathway may contribute to NK cell suppression within tumors.
  • Poxin, a viral protein, degrades cyclic GMP-AMP (cGAMP) and could potentially mitigate DNA sensing-induced stress in NK cells.

Purpose of the Study:

  • To investigate if Poxin expression can inhibit DNA sensing pathways in NK cells.
  • To determine if Poxin enhances NK cell cytotoxic function and anti-tumor activity.

Main Methods:

  • Generated NK-92 cells expressing a Poxin transgene.
  • Stimulated the cGAS-STING pathway using plasmid transfection or irradiation to induce double-stranded DNA (dsDNA).
  • Assessed NK cell activity, perforin and granzyme B levels, performed RNA-seq, and evaluated anti-tumor efficacy of Poxin-expressing NK-92 and CAR-NK-92 cells.

Main Results:

  • Poxin expression significantly inhibited the cGAS-STING pathway activation by dsDNA.
  • RNA-seq revealed increased cytotoxic mediators (perforin, granzyme B) in Poxin-expressing NK-92 cells.
  • Transgenic NK-92/CAR-NK-92 cells demonstrated enhanced anti-tumor activity compared to controls.

Conclusions:

  • Poxin effectively suppresses DNA sensing-mediated innate immunity in NK cells.
  • Poxin enhances NK cell cytotoxicity and anti-tumor effectiveness.
  • Poxin represents a potential strategy to improve NK cell-based cancer immunotherapies.
Keywords:
Cell therapyDNA sensingNatural killer cellsPoxin

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