肝细胞癌（HCC）是最常见的原发性肝癌类型。转化生长因子β (TGF-β) 在肝脏肿瘤微环境中高表达，已知可抑制免疫细胞活性。在这里，我们使用人类诱导多能干细胞 (iPSC) 来产生自然杀伤 (NK) 细胞，这些细胞经过改造可介导改善的抗 HCC 活性。具体来说，我们生产了敲除 TGF-β 受体 2 (TGFBR2-KO) 或表达显性失活 (DN) 形式的 TGF-β 受体 2 (TGFBR2-DN) 与嵌合抗原受体 (CAR) 结合的 iPSC-NK 细胞。 ），以 GPC3 或 AFP 为目标。 TGFBR2-KO 和 TGFBR2-DN iPSC-NK 细胞对 TGF-β 抑制具有抵抗力，并提高了抗 HCC 活性。然而，在 iPSC-NK 细胞上表达抗 HCC CAR 并不会产生有效的抗 HCC 活性，除非同时抑制 TGF-β 活性。我们的研究结果表明，TGF-β 信号传导阻断是 NK 细胞发挥有效功能以对抗 HCC 和表达高水平 TGF-β 的其他潜在恶性肿瘤所必需的。版权所有 © 2024 Elsevier Inc. 保留所有权利。

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Transforming growth factor beta (TGF-β) is highly expressed in the liver tumor microenvironment and is known to inhibit immune cell activity. Here, we used human induced pluripotent stem cells (iPSCs) to produce natural killer (NK) cells engineered to mediate improved anti-HCC activity. Specifically, we produced iPSC-NK cells with either knockout TGF-β receptor 2 (TGFBR2-KO) or expression of a dominant negative (DN) form of the TGF-β receptor 2 (TGFBR2-DN) combined with chimeric antigen receptors (CARs) that target either GPC3 or AFP. The TGFBR2-KO and TGFBR2-DN iPSC-NK cells are resistant to TGF-β inhibition and improved anti-HCC activity. However, expression of anti-HCC CARs on iPSC-NK cells did not lead to effective anti-HCC activity unless there was also inhibition of TGF-β activity. Our findings demonstrate that TGF-β signaling blockade is required for effective NK cell function against HCC and potentially other malignancies that express high levels of TGF-β.Copyright © 2024 Elsevier Inc. All rights reserved.