Key Mechanisms of NK Cell Dysfunction Revealed

A team led by Wei Haiming, MS, MD, professor, Zheng Xiaohu, professor, and Tian Zhigang, professor, all from the University of Science and Technology (USTC), revealed the key mechanism of the loss of membrane protrusions on intratumoral natural killer (NK) cells, which impairs their ability to recognize and kill tumor cells. This work, published recently in Nature Immunology, provides a new strategy for NK cell-based immunotherapy.

NK cells play a crucial role in immunotherapy. However, their ability to kill tumor cells is severely compromised in the tumor microenvironment and most advanced-stage tumors can evade the immune attack of NK cells. In order to restore the function of the intratumoral NK cells, it is important to understand the mechanism of their impairments.

The team used both transmission electron microscopy (TEM) and scanning electron microscopy (SEM) to clearly observe the distinct difference in the surface topology of NK cells’ membranes in normal and tumor microenvironments. The membrane surfaces of normal NK cells have abundant protrusions, while the membrane surfaces of intratumoral NK cells are abnormally smooth, displaying very few protrusions.

Further research revealed that normal NK cells use membrane protrusions to recognize and form immunological synapses with tumor cells, through which the NK cells release granzymes to lyse tumor cells. With the loss of membrane protrusions, intratumoral NK cells from patients with advanced-stage cancer are unable to recognize and form contact with tumor cells, thereby losing the ability to kill tumor cells.

The team also developed a single-immunocyte mass spectrometry (MS) technology, which can detect the changes in the chemical components of intratumoral NK cell membranes—mainly the decrease in sphingomyelin (SM)—confirming that the dysregulated serine metabolism in tumors is the main cause of the decrease in SM. 

Sphingomyelinase inhibitors can significantly increase the SM in intratumoral NK cell membranes, which can restore protrusion formation and improve NK cells’ ability to recognize and kill tumor cells. Results show that targeting sphingomyelinase demonstrates powerful synergistic antitumor efficacy when combined with immune checkpoint-targeted therapy.

- This press release was originally published on the University of Science and Technology of China website