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Updated: Feb 24, 2026

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Refined Modulation of Natural Killer Cells by Transforming Growth Factor-β Isoforms

Kaku Goto1,2, Ryo Amano1, Yoshikazu Nakamura1,3

  • 1Project Division of RNA Medical Science, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Genes to Cells : Devoted to Molecular & Cellular Mechanisms
|February 23, 2026
PubMed

Insights

Transforming growth factor-beta 3 (TGF-β3) uniquely upregulates INAVA in natural killer (NK) cells, enhancing their cancer-fighting ability. This discovery offers new avenues for cancer immunotherapy by selectively targeting TGF-β isoforms.

Area of Science:

  • Immunology
  • Cancer Biology
  • Molecular Biology

Background:

  • Natural killer (NK) cells are crucial for anti-tumor immunity.
  • The tumor microenvironment, particularly transforming growth factor-beta (TGF-β), suppresses NK cell activity.
  • Distinct functions of TGF-β isoforms (TGF-β1, TGF-β2, TGF-β3) are increasingly recognized.

Purpose of the Study:

  • To elucidate the specific effects of TGF-β isoforms on NK cells.
  • To identify novel regulators of NK cell function modulated by TGF-β isoforms.
  • To explore the therapeutic potential of selective TGF-β isoform modulation.

Main Methods:

  • Genome-wide gene expression analysis to identify TGF-β isoform-specific targets.
  • Investigated the effect of TGF-β3 on innate immunity activator (INAVA) expression.
  • Assessed the impact of INAVA on interferon gamma (IFN-γ) signaling and NK cell cytotoxicity.
  • Evaluated an anti-TGF-β1 aptamer's effect on INAVA upregulation.
  • Analyzed clinical data correlating INAVA expression with tumor-infiltrating NK (TINK) cells and patient survival in melanoma.

Main Results:

  • TGF-β3 uniquely upregulates INAVA in NK cells, distinct from TGF-β1 and TGF-β2.
  • INAVA enhances IFN-γ signaling, boosting NK cell IFN-γ release and cytotoxicity against cancer cells.
  • An anti-TGF-β1 aptamer preserved TGF-β3-mediated INAVA upregulation.
  • Increased INAVA expression correlated with activated TINK cells and improved survival in melanoma patients.

Conclusions:

  • TGF-β3 exerts a unique immunomodulatory function on NK cells via INAVA.
  • Selective modulation of TGF-β isoforms, particularly TGF-β3, represents a promising immunotherapeutic strategy.
  • Targeting the TGF-β3-INAVA pathway may enhance NK cell-based cancer therapies.
Keywords:
INAVANK cellTGF‐βaptamerimmunotherapyinnate immunity activatorisoformtumor microenvironment

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