Reporters learned from the University of Science and Technology of China on the 26th that Professor Wei Haiming, Professor Zheng Xiaohu and Professor Tian Zhigang from the National Research Center for Micro scale Material Science and the Department of Life Sciences and Medicine of the University cooperated with Qian Yeben, the director of the First Affiliated Hospital of Anhui Medical University, and found that the tumor tissue microenvironment natural killer (NK) cells lost their facial mask protuberance, could not identify tumor cells, and lost their anti-tumor function. They also created a "single immune cell membrane mass spectrometry detection technology", revealing that the loss of sphingomyelin, the main component of NK cell membrane, is the main reason for the loss of surface protrusions on NK cells. The relevant research results were recently published online in the journal Nature Immunology. NK cells are the "professional killers" of tumors and play a pivotal role in anti-tumor immunotherapy. However, in the tumor microenvironment, the anti-tumor function of NK cells is seriously challenged, and most advanced tumors can escape the killing of NK cells. It is urgent to understand the mechanism and find new ways to restore the function of NK cells. Using transmission and scanning electron microscopy techniques, researchers have found that there are significant differences in the topological morphology of NK cell membranes in the microenvironment of normal and tumor tissues. There are abundant protrusions on the surface of normal NK cell membranes, while the surface of NK cell membranes in the microenvironment of tumor tissues is unusually smooth, with significant loss of protrusions. Further exploration has found that normal NK cells use membrane processes to recognize and capture tumor cells, and promote cell to cell interactions to form "immune synapses" that play a role in killing tumor cells. This immune synapse is a special intercellular structure formed between NK cells and tumor cells. NK cells lyse and kill tumor cells through immune synaptic release of granular enzymes. The researchers also created a "single immune cell membrane mass spectrometry detection technology", and found that the membrane components of NK cells in the tumor microenvironment changed, mainly due to a significant decrease in the content of sphingomyelin. They also confirmed that the imbalance in serine metabolism in the tumor microenvironment was the main cause of the decline in sphingomyelin. Using inhibitors targeting sheath phospholipase can significantly increase the content of sphingomyelin in the NK cell membrane of the tumor microenvironment, restore protrusion formation, and improve the recognition and killing ability of tumor cells. Targeted sheath phospholipase intervention combined with immune checkpoint blockers has a synergistic anticancer effect. This study, from a new perspective of cell membrane topology, explains the new mechanisms of dysfunction and immune escape of tumor derived NK cells, and provides a new strategy for improving the immunotherapy of NK cells. (Liao Xinshe)