Advancing NK Cells: Enhancing Tumor Targeting and Killing

Michael Caligiuri, MD, professor in the Division of Leukemia, Department of Hematology & Hematopoietic Cell Transplantation at City of Hope, discusses the modulation of natural killer (NK) cells to enhance their ability to detect and destroy tumor cells.

According to Caligiuri, NK cells are an essential part of the immune system, naturally equipped to eliminate abnormal or cancerous cells. However, their effectiveness is often limited by a lack of precise targeting and built-in safety mechanisms that prevent them from attacking the body’s own tissues. Recent scientific advances are changing that.

One major breakthrough involves equipping NK cells with chimeric antigen receptors (CARs). These are lab-designed receptors that enable NK cells to recognize specific markers (or “flags”) on the surface of cancer cells. This allows NK cells to effectively “see” and seek out tumors that would otherwise remain hidden in the body. Once the CAR-modified NK cell reaches the tumor, it delivers a strong signal to attack, significantly improving its tumor-killing ability.

But simply directing the NK cell to the tumor is not always enough. NK cells also have built-in inhibitory signals, or “stop signs,” as Caligiuri says, that can prevent them from fully activating, especially when the tumor closely resembles normal tissue. To overcome this, experts are also working to remove these inhibitory pathways, essentially lifting the brakes on NK cell function. This two-part strategy, which involves adding tumor-targeting receptors and removing inhibitory controls, creates a more decisive and aggressive NK cell response.

This evolving approach is showing promise across various cancers, including leukemia, lung, and pancreatic tumors, and represents a shift in how cell-based immunotherapies are being designed.

For community oncologists, this research underscores the potential of next-generation NK cell therapies to offer targeted, off-the-shelf options that could complement or enhance existing treatment regimens—particularly in patients with hard-to-treat malignancies.

“So, the most exciting thing in the field is to modulate—change—NK cells. Taking what Mother Nature gave you and kind of capitalizing on it, and making it even more ferocious of a killer for cancer,” he adds.