Natural Killer (NK) cells are a critical component of the innate immune system and play an essential role in recognizing and eliminating cancer cells. Despite their promise, current NK-based therapies, including CAR-NK approaches, face major challenges in solid tumors due to limited infiltration, poor persistence, and functional exhaustion within the tumor microenvironment.

To address these barriers, we applied in vivo CRISPR knockout screening to primary NK cells, establishing an unbiased functional genomics platform to systematically uncover regulators of NK activity. Through this approach, we identified CALHM2, a previously unrecognized NK cell immune checkpoint. Strikingly, knockout of CALHM2 enhanced NK cell tumor infiltration and cytotoxicity, thereby improving anti-tumor responses in preclinical models.

In this presentation, I will discuss how CRISPR-based functional genomics enables the discovery of NK-specific regulators and outline strategies to translate these findings into next-generation CAR-NK therapies with improved efficacy against solid tumors.

Learning Objectives:

1. Describe the major challenges limiting the efficacy of CAR-NK therapies in solid tumors.

2. Explain how in vivo CRISPR knockout screening can be used to identify regulators of NK cell activity.

3. Identify CALHM2 as a novel NK cell immune checkpoint and its role in modulating NK cell function.