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<p>Transforming growth factor beta (TGFβ) and activin A suppress natural killer (NK) cell function and proliferation, limiting the efficacy of adoptive NK cell therapies. Inspired by the partial resistance to TGFβ of NK cells with <i>SMAD4</i> haploinsufficiency, we used CRISPR–Cas9 for knockout of <i>SMAD4</i> in human NK cells. Here we show that <i>SMAD4</i><sup>KO</sup> NK cells were resistant to TGFβ and activin A inhibition, retaining their cytotoxicity, cytokine secretion and interleukin-2/interleukin-15-driven proliferation. They showed enhanced tumor penetration and tumor growth control, both as monotherapy and in combination with tumor-targeted therapeutic antibodies. Notably, <i>SMAD4</i><sup>KO</sup> NK cells outperformed control NK cells treated with a TGFβ inhibitor, underscoring the benefit of maintaining SMAD4-independent TGFβ signaling. <i>SMAD4</i><sup>KO</sup> conferred TGFβ resistance across diverse NK cell platforms, including CD19-CAR NK cells, stem cell-derived NK cells and ADAPT-NK cells. These findings position <i>SMAD4</i> knockout as a versatile and compelling strategy to enhance NK cell antitumor activity, providing a new avenue for improving NK cell-based cancer immunotherapies.</p>

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Enhancing human NK cell antitumor function by knocking out SMAD4 to counteract TGFβ and activin A suppression

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年3月21日

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  • Anna Rea,
  • Sara Santana-Hernández,
  • Javier Villanueva,
  • Marta Sanvicente-García,
  • Mariona Cabo,
  • Jesús Suarez-Olmos,
  • Fabricio Quimis,
  • Mengjuan Qin,
  • Eduard Llorens,
  • Sandra Blasco-Benito,
  • Lamberto Torralba-Raga,
  • Lorena Perez,
  • Bishan Bhattarai,
  • Elisenda Alari-Pahissa,
  • Anna-Maria Georgoudaki,
  • Francesc Balaguer,
  • Manel Juan,
  • Julián Pardo,
  • Toni Celià-Terrassa,
  • Ana Rovira,
  • Nina Möker,
  • Congcong Zhang,
  • Marco Colonna,
  • Jan Spanholtz,
  • Karl-Johan Malmberg,
  • Clara Montagut,
  • Joan Albanell,
  • Marc Güell,
  • Miguel López-Botet,
  • Aura Muntasell

摘要

Transforming growth factor beta (TGFβ) and activin A suppress natural killer (NK) cell function and proliferation, limiting the efficacy of adoptive NK cell therapies. Inspired by the partial resistance to TGFβ of NK cells with SMAD4 haploinsufficiency, we used CRISPR–Cas9 for knockout of SMAD4 in human NK cells. Here we show that SMAD4KO NK cells were resistant to TGFβ and activin A inhibition, retaining their cytotoxicity, cytokine secretion and interleukin-2/interleukin-15-driven proliferation. They showed enhanced tumor penetration and tumor growth control, both as monotherapy and in combination with tumor-targeted therapeutic antibodies. Notably, SMAD4KO NK cells outperformed control NK cells treated with a TGFβ inhibitor, underscoring the benefit of maintaining SMAD4-independent TGFβ signaling. SMAD4KO conferred TGFβ resistance across diverse NK cell platforms, including CD19-CAR NK cells, stem cell-derived NK cells and ADAPT-NK cells. These findings position SMAD4 knockout as a versatile and compelling strategy to enhance NK cell antitumor activity, providing a new avenue for improving NK cell-based cancer immunotherapies.