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

ABSTRACT: 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 SMAD4^KO 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, SMAD4^KO NK cells outperformed control NK cells treated with a TGFβ inhibitor, underscoring the benefit of maintaining

SUBMITTER: Rea A 

PROVIDER: S-EPMC11957989 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature