肿瘤细胞治疗研究
英文原题：An innovative strategy harnessing self-activating CAR-NK cells to mitigate TGF-β1-driven immune suppression.
由肿瘤微环境中的转化生长因子 1（TGF 1）介导的自然杀伤（NK）细胞功能障碍，会阻碍抗肿瘤治疗并导致不良临床结局。
肿瘤微环境中的转化生长因子 β1（TGF-β1）介导自然杀伤（NK）细胞功能障碍，阻碍抗肿瘤治疗并导致临床结局不佳。本研究提出一种自激活嵌合抗原受体（CAR）NK 细胞，可释放特异设计的肽 P6 阻断 TGF-β1 信号，并靶向胰腺肿瘤中的间皮素。P6 来源于 TGF-β1 与 TGF-β 受体 1 的相互作用位点，可有效破坏 TGF-β1 对 NK 细胞的抑制信号。分析显示，P6 处理可中断 NK 细胞中的 SMAD2/3 通路，减轻 TGF-β1 介导的 NK 细胞活性抑制，从而增强其代谢功能及对胰腺肿瘤的细胞毒性应答。这些 CAR-NK 细胞在含癌症相关成纤维细胞的球体培养体系和小鼠体内模型中均显示强效抗肿瘤能力。本方法在克服 TGF-β1 介导的免疫逃逸方面取得了重要进展，为革新癌症免疫治疗提供了有前景的新方向。
The dysfunction of natural killer (NK) cells, mediated by transforming growth factor 1 (TGF 1) within the tumor microenvironment, impedes antitumor therapy and contributes to poor clinical outcomes. Our study introduces self-activating chimeric antigen receptor (CAR)-NK cells that block TGF 1 signaling by releasing a specifically designed peptide, P6, which targets mesothelin in pancreatic tumors. P6 originates from the interaction sites between TGF 1 and TGF receptor 1 and effectively disrupts TGF 1's inhibitory signaling in NK cells. Our analysis demonstrates that P6 treatment interrupts the SMAD2/3 pathway in NK cells, mitigating TGF 1-mediated suppression of NK cell activity, thereby enhancing their metabolic function and cytotoxic response against pancreatic tumors. These CAR-NK cells exhibit potent antitumor capabilities, as evidenced in spheroid cultures with cancer-associated fibroblasts and in vivo mouse models. Our approach marks a substantial advancement in overcoming TGF 1-mediated immune evasion, offering a promising avenue for revolutionizing cancer immunotherapy.
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