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Updated: Feb 26, 2026

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TNFR2 signaling promotes monocytic-MDSC differentiation and production of immunosuppressive mediators

Yuta Tsuji1, Masaki Inoue1, Tomoya Okuda1

  • 1The Faculty of Pharmaceutical Sciences, Laboratory of Cellular and Molecular Physiology, Kobe Gakuin University, Japan.

FEBS Letters
|February 25, 2026
PubMed

Insights

Tumor-promoting myeloid-derived suppressor cells (MDSCs) rely on TNF receptor type 2 (TNFR2) signaling. Targeting TNFR2 can modulate MDSC function and potentially enhance cancer therapy by reducing immunosuppression.

Area of Science:

  • Immunology
  • Cancer Biology
  • Cell Signaling

Background:

  • Myeloid-derived suppressor cells (MDSCs) are key regulators of the tumor microenvironment, promoting cancer progression and therapeutic resistance.
  • MDSCs express high levels of TNF receptor type 2 (TNFR2), but its specific function is obscured by the dual action of TNF-α on TNFR1 and TNFR2.

Purpose of the Study:

  • To investigate the specific role of TNFR2 signaling in the function and differentiation of MDSCs.
  • To evaluate TNFR2 as a potential therapeutic target for modulating MDSC-mediated immunosuppression in cancer.

Main Methods:

  • Utilized TNFR2-knockout mice to generate GM-CSF-induced MDSCs.
  • Employed a TNFR2-selective agonist (scR2agoTNF-Fc) to stimulate MDSCs.
  • Assessed the impact of TNFR2 modulation on MDSC suppressive capacity and effector molecule expression.

Main Results:

  • TNFR2 activation maintained a highly suppressive monocytic MDSC subset.
  • TNFR2 deficiency significantly reduced MDSC-mediated suppression of T-cell responses.
  • TNFR2 signaling upregulated key immunosuppressive molecules, including inducible nitric-oxide synthase (iNOS) and interleukin-10 (IL-10).

Conclusions:

  • TNFR2 plays a critical role in maintaining the immunosuppressive functions of MDSCs.
  • Targeting TNFR2 represents a promising therapeutic strategy to counteract MDSC-driven immune suppression in cancer.
Keywords:
IL‐10ImmunosuppressionMDSCTNFR2TNF‐αiNOS

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