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PAD2-mediated citrullination of STAT3 enhances immunosuppressive function of PMN-MDSCs in tumor-bearing hosts

Yi Teng1, Yuhang Chen2, Xueli Xia2

  • 1Department of Laboratory Medicine, Jiangsu Province Engineering Research Center for Precise Diagnosis and Treatment of Inflammatory Diseases, Affiliated Hospital, Jiangsu University, Zhenjiang, China; Department of Immunology, Jiangsu Key Laboratory for Laboratory Medicine, Jiangsu University School of Medicine, Zhenjiang, China; Department of Laboratory Medicine, Affiliated Jurong Hospital, Jiangsu University, Zhenjiang, China.

International Immunopharmacology
|August 6, 2025
PubMed

Insights

Peptidylarginine deiminase 2 (PAD2) enhances myeloid-derived suppressor cells (MDSCs) immunosuppressive function by citrullinating STAT3, promoting tumor growth. PAD2 inhibition reduces MDSC activity and tumor progression.

Area of Science:

  • Immunology
  • Cancer Biology
  • Biochemistry

Background:

  • Myeloid-derived suppressor cells (MDSCs) are critical regulators of antitumor immunity, facilitating tumor immune evasion.
  • Citrullination, a posttranslational protein modification, is implicated in tumorigenesis and cancer development.

Purpose of the Study:

  • To investigate the role of citrullination in regulating the function of MDSCs within the tumor microenvironment.
  • To elucidate the specific contribution of peptidylarginine deiminase 2 (PAD2) in modulating MDSC immunosuppressive activities.

Main Methods:

  • Analysis of MDSC immunosuppressive function via co-culture with CD8+ T cells.
  • In vitro and in vivo assessment of MDSC phenotype and function following PAD2 knockdown.
  • Investigation of PAD2-mediated STAT3 citrullination using immunoprecipitation and immunofluorescence.

Main Results:

  • PAD2 knockdown significantly reduced the immunosuppressive function and Arginase-1 (Arg-1) expression of polymorphonuclear MDSCs (PMN-MDSCs).
  • PAD2-mediated citrullination of STAT3 was identified as a mechanism promoting Arg-1 transcription.
  • PAD2 inhibition attenuated the protumorigenic capabilities of PMN-MDSCs in a tumor-bearing mouse model.

Conclusions:

  • PAD2 enhances MDSC immunosuppressive function through STAT3 citrullination, leading to increased Arg-1 expression.
  • Targeting PAD2 presents a potential therapeutic strategy to counteract MDSC-mediated immunosuppression and inhibit tumor development.
Keywords:
CitrullinationMyeloid-derived suppressor cellsPAD2Tumor immunity

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