Shin, Seung hun Lee, Young Eun Yoon, Han-Na Yuk, Chae Min An, Jun Yop Seo, Minkoo Yoon, Sangwon Oh, Min-Suk Shin, Sang Chul Kim, Ji Hyung Kim, Yong Jun Kim, Jin-Chul Kim, Song Cheol Jang, Mihue 2024-10-21T03:00:08Z 2024-10-21T03:00:08Z 2024-10-19 2025-03 0142-9612 https://pubs.kist.re.kr/handle/201004/150825 The dysfunction of natural killer (NK) cells, mediated by transforming growth factor β1 (TGFβ1) 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 TGFβ1 signaling by releasing a specifically designed peptide, P6, which targets mesothelin in pancreatic tumors. P6 originates from the interaction sites between TGFβ1 and TGFβ receptor 1 and effectively disrupts TGFβ1's inhibitory signaling in NK cells. Our analysis demonstrates that P6 treatment interrupts the SMAD2/3 pathway in NK cells, mitigating TGFβ1-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 TGFβ1-mediated immune evasion, offering a promising avenue for revolutionizing cancer immunotherapy. English Pergamon Press Ltd. An innovative strategy harnessing self-activating CAR-NK cells to mitigate TGF-β1-driven immune suppression Article 10.1016/j.biomaterials.2024.122888 1 Biomaterials, v.314 Biomaterials 314 N scie scopus 001338924400001 Engineering, Biomedical Materials Science, Biomaterials Engineering Materials Science Article EPITHELIAL-MESENCHYMAL TRANSITION NATURAL-KILLER-CELLS TGF-BETA RECEPTOR FIBROBLASTS CANCER MESOTHELIN PANCREAS ADENOCARCINOMAS IMMUNOTHERAPY EXPRESSION Natural killer cell Chimeric antigen receptor TGF(3 Solid tumor Tumor microenvironment