Anti-tumor function was assessed using AsPC-1 cancer killing assays, patient-derived pancreatic cancer organoids (caspase-3/7 imaging, luciferase viability, live/dead FACS), and multi-omics profiling (RNA-seq, ATAC-seq, GSEA) to evaluate metabolic and transcriptional modifications.<h4>Results</h4>We report a streamlined, one-step strategy that simultaneously disrupts the TGFβ receptor II (TGFβRII) and integrates a mesothelin-targeting CAR transgene into primary NK cells via electroporation. Here, MSLN is linked to familial pancreatic carcinoma.