ArticleTheranostics2026
One-step knock-in CAR constructs in human NK cells enable scalable, TGFβ1-resistant immunotherapy for solid tumors.
Article in Theranostics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Rationale: Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells represent a promising modality for cancer immunotherapy, yet their efficacy in solid tumors is limited by immunosuppressive cues from the tumor microenvironment (TME), particularly, transforming growth factor β (TGFβ). Methods: Primary human NK cells were cytokine-activated (IL-12/15/18) and engineered via a one-step electroporation that delivered Cas9 ribonucleoprotein and a dsDNA donor (1 kb homology arms, SFFV promoter, poly(A), GRE element) to knock out TGFBR2 and knock in a mesothelin CAR. We compared against a two-step AAV method, and treated dexamethasone (Dex) during manufacture. 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. Results: 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. By optimizing single-guide RNAs, donor DNA templates incorporating glucocorticoid response elements, and electroporation parameters, we achieved markedly improved knock-in efficiency. Transient Dex treatment during genome editing enhanced CAR expression and cytotoxic function in both electroporation- and AAV-mediated platforms. Dex augmented the cytotoxic activity of CAR-NK cells by promoting oxidative phosphorylation and ATP production. Conclusions: We designed robust, TGFβ1-resistant allogeneic CAR-NK cells using a virus-free, one-step engineering strategy, establishing a versatile, clinically scalable method for engineering metabolically fortified CAR-NK cells capable of overcoming TME-mediated suppression in solid tumors.
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