Genome-wide CRISPR screens in primary human natural killer cells identify countermeasures against immunosuppressive environment.
basic_science · Level V
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- Record sourced from PubMed, PMID 41986330.
- Also identified by DOI 10.1038/s41467-026-71895-x.
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Abstract
Natural killer (NK) cells are promising effectors for cancer immunotherapy, but their efficacy is limited by immunosuppressive tumor microenvironments. To uncover strategies for enhancing NK cell function, we establish a CRISPR loss-of-function screening platform for primary human NK cells by combining BaEVRless-pseudotyped lentiviral transduction of sgRNA libraries with Cas9 protein electroporation. This platform enables genome-scale interrogation of gene function in non-transformed NK cells. Kinome-focused and genome-wide screens identify key regulators of NK cell proliferation, cytotoxicity, and resistance to prostaglandin E<sub>2</sub> (PGE<sub>2</sub>)-mediated suppression. STK17B deletion enhances NK cell expansion, while loss of CCDC53 boosts degranulation and cytotoxicity. We also uncover the CRL5 complex-including RNF7, UBE2F, and CISH-as critical inhibitors of IL-2 signaling and effector function under PGE<sub>2</sub> stress. These findings establish a scalable platform for CRISPR-based functional genomics in primary NK cells and reveal engineering targets to enhance NK cell persistence and efficacy in tumor microenvironments.