Faculty, Staff and Student Publications

Language

English

Publication Date

11-10-2025

Journal

Cancer Cell

DOI

10.1016/j.ccell.2025.07.021

PMID

40845844

PMCID

PMC12396527

PubMedCentral® Posted Date

10-17-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Adoptive cell therapy using engineered natural killer (NK) cells is a promising approach for cancer treatment, with targeted gene editing offering the potential to further enhance their therapeutic efficacy. However, the spectrum of actionable genetic targets to overcome tumor and microenvironment-mediated immunosuppression remains largely unexplored. We performed multiple genome-wide CRISPR screens in primary human NK cells and identified critical checkpoints regulating resistance to immunosuppressive pressures. Ablation of MED12, ARIH2, and CCNC significantly improved NK cell antitumor activity against multiple treatment-refractory human cancers in vitro and in vivo. CRISPR editing augmented both innate and CAR-mediated NK cell function, associated with enhanced metabolic fitness, increased secretion of proinflammatory cytokines, and expansion of cytotoxic NK cell subsets. Through high-content genome-wide CRISPR screening in NK cells, this study reveals critical regulators of NK cell function and provides a valuable resource for engineering next-generation NK cell therapies with improved efficacy against cancer.

Keywords

Humans, Killer Cells, Natural, Immunotherapy, Adoptive, Animals, Gene Editing, Mice, CRISPR-Cas Systems, Receptors, Chimeric Antigen, Neoplasms, Clustered Regularly Interspaced Short Palindromic Repeats, Xenograft Model Antitumor Assays, Cell Line, Tumor, Tumor Microenvironment, CAR-NK cell therapy, genome-wide CRISPR screens, tumor microenvironment, adoptive cell therapy, natural killer cells, solid tumors, multiplexed cellular engineering, metabolic reprogramming, precision gene editing, functional perturbomics

Published Open-Access

yes

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