An innovative strategy harnessing self-activating CAR-NK cells to mitigate TGF-β1-driven immune suppression

• Published in: Biomaterials 2025-03, Vol.314, p.122888, Article 122888
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Chimeric antigen receptor; Humans; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Mesothelin; Mice; Natural killer cell; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - therapy; Receptors, Chimeric Antigen - immunology; Receptors, Chimeric Antigen - metabolism; Signal Transduction; Solid tumor; TGFβ; Transforming Growth Factor beta1 - metabolism; Tumor microenvironment; Tumor Microenvironment - immunology
• ISSN: 0142-9612; 1878-5905; 1878-5905
• DOI: 10.1016/j.biomaterials.2024.122888

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. [Display omitted]