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通过敲除SMAD4以对抗转化生长因子β（TGFβ）和激活素A的抑制作用来增强人类自然杀伤细胞的抗肿瘤功能。

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

作者信息

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

机构信息

University Pompeu Fabra (UPF), Barcelona, Spain.

Hospital del Mar Research Institute (IMIM), Barcelona, Spain.

出版信息

Nat Immunol. 2025 Apr;26(4):582-594. doi: 10.1038/s41590-025-02103-z. Epub 2025 Mar 21.

DOI:10.1038/s41590-025-02103-z
PMID:40119192
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11957989/
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 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 NK cells outperformed control NK cells treated with a TGFβ inhibitor, underscoring the benefit of maintaining SMAD4-independent TGFβ signaling. SMAD4 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.

摘要

转化生长因子β（TGFβ）和激活素A会抑制自然杀伤（NK）细胞的功能和增殖，从而限制过继性NK细胞疗法的疗效。受SMAD4单倍体不足的NK细胞对TGFβ具有部分抗性的启发，我们使用CRISPR-Cas9敲除了人类NK细胞中的SMAD4。在此我们表明，SMAD4缺陷型NK细胞对TGFβ和激活素A的抑制具有抗性，保留了它们的细胞毒性、细胞因子分泌以及白细胞介素-2/白细胞介素-15驱动的增殖能力。无论是作为单一疗法还是与肿瘤靶向治疗性抗体联合使用，它们都表现出增强的肿瘤浸润和肿瘤生长控制能力。值得注意的是，SMAD4缺陷型NK细胞的表现优于用TGFβ抑制剂处理的对照NK细胞，这突出了维持不依赖SMAD4的TGFβ信号传导的益处。SMAD4在包括CD19嵌合抗原受体NK细胞、干细胞衍生的NK细胞和ADAPT-NK细胞在内的多种NK细胞平台上都赋予了对TGFβ的抗性。这些发现表明，敲除SMAD4是增强NK细胞抗肿瘤活性的一种通用且有吸引力的策略，为改进基于NK细胞的癌症免疫疗法提供了一条新途径。

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