An innovative strategy harnessing self-activating CAR-NK cells to mitigate TGF-(31-driven immune suppression

초록

The dysfunction of natural killer (NK) cells, mediated by transforming growth factor (31 (TGF(31) 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(31 signaling by releasing a specifically designed peptide, P6, which targets mesothelin in pancreatic tumors. P6 originates from the interaction sites between TGF(31 and TGF(3 receptor 1 and effectively disrupts TGF(31's inhibitory signaling in NK cells. Our analysis demonstrates that P6 treatment interrupts the SMAD2/3 pathway in NK cells, mitigating TGF(31mediated 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(31-mediated immune evasion, offering a promising avenue for revolutionizing cancer immunotherapy.

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