Immune checkpoint blockade (ICB) is an important cancer therapy, but unfortunately, its response rate is low - significant for a few patients who respond, but difficult to achieve for most patients. Therefore, how to improve the response rate of ICB therapy has become a key issue in cancer treatment. Recently, researchers Wang Hai and Nie Guangjun from the National Center for Nanoscience and Technology collaborated with Professor Ran Haitao's team from Chongqing Medical University to develop three metal ion coordinated phenylalanine nanostructures. This new structure can effectively reshape the immunosuppressive microenvironment of tumors, significantly improving the response rate of ICB therapy and expanding the scope of tumor immunotherapy. The relevant research results were published in Nature Nanotechnology. The basic mechanism of ICB therapy is to activate the immune system, "Wang Hai told reporters." The human body has two immune defense lines. The first defense line is the innate immune system, which can directly eliminate foreign pathogens and prevent bacteria and viruses from infecting the body. When the first defense line fails, the body will activate the second defense line - the adaptive immune system. In this case, white blood cells and T cells will enhance the immune response and participate in clearing foreign substances. This mechanism provides an important background for understanding ICB therapy. "The immune system plays an important role in protecting human health. But cunning tumor cells can use the binding of programmed death receptors and their ligands to escape host immune killing. Therefore, programmed death receptors and their ligands are referred to as "immune checkpoints". ICB therapy enhances the host immune system's ability to recognize and attack tumor cells by inhibiting the binding of programmed death receptors to ligands. Over the past decade, people have been searching for ways to activate immune responses. Through extensive research and experiments, scientists have discovered two main activation modes - pathogen related molecular mode and damage related molecular mode, but the activation efficiency is not ideal. Therefore, finding new activation mechanisms has become the focus of current research. The innovation of this study is the exploration of a new activation mode - regulating immune function through metal ions Wang Hai said. The research team synthesized nanostructures coordinated with magnesium, iron, and zinc ions and phenylalanine to alter the pore size of ion channels in immune cells. By activating these channels, potassium ion efflux is promoted, leading to calcium ion influx and inducing related immune signaling pathways, improving the microenvironment of tumor immune suppression. Coincidentally, this activation mode can simultaneously improve both innate and adaptive immune protection systems Wang Hai said, "On the one hand, it improves the immune microenvironment, and on the other hand, it enhances adaptive immune ability, promoting specific killing cells to attack tumor cells." His mind was "lit up" by a sentence. In 2018, while reading a review article, Wang Hai was attracted by a sentence: "The function of immune cells is closely related to the entry of metal ions." "Can the immune response of cells be regulated by metal ions?" Wang Hai suddenly had this idea, "Because he had been thinking about immune regulation at that time, he felt that his mind was suddenly" lit up "by this sentence." After multiple discussions with his team members, Wang Hai and his team believed that this idea was feasible and should be tried. The key to this study is the regulation of metal ion channels. At the beginning, the team designed a large number of experiments to deliver metal ions into cells, attempting to regulate the entry and exit of potassium and calcium ions in dendritic cells. At that time, we spent a lot of time researching literature and conducting a large number of experiments Wang Hai said, "Although people can inhibit the entry and exit of metal ions into cells through some drugs, there is a lack of effective means to activate these channels." In the experiment, researchers found that certain metal ions have a certain regulatory effect, but did not reach the ideal state. Meanwhile, they learned that in clinical practice, cancer chemotherapy has used nutritional control to enhance the efficacy of immunotherapy. After connecting these ideas, the researchers decided to enhance the immune activation effect by combining metal ions and nanostructures to strengthen nutrition. Therefore, assembling different metal ions and amino acids and verifying whether they can open ion channels has become the second key point of this study. In early 2019, Wang Hai led a team to screen nanostructures combining metal ions and amino acids, but setbacks always followed closely. Researchers arrange and combine metal ions and amino acids to form nanostructures and verify their effects one by one. But testing and verifying a combination takes two to three days from preparation to completion of the experiment. There are many metal ions and various types of amino acids, and this continuous process of arranging, pairing, combining, and trial and error consumes a lot of time for the team. In research, the vast majority of experiments do not show any results, so we have to tirelessly try again and again Wang Hai said, 'The experiment has been going on for almost half a year, but still nothing has been achieved.' Hard work pays off. At the end of 2019, the research team prepared three types of nanostructures by coordinating magnesium ions, ferrous ions, and zinc ions with L-phenylalanine in experiments. Interestingly, although the nanostructures formed by these three metal ions have been discovered one after another, their shapes are completely different. The magnesium ion structure is spherical, the ferrous ion structure is rod-shaped, and the zinc ion structure is sheet-like. The experiment found that all three types of nanostructures have the effect of activating potassium ion channels on dendritic cell membranes. We basically saw activation effects on three structures at the same time Tan Mishiao, co first author of the paper and a PhD graduate jointly trained by the National Center for Nanoscience and Technology, said, "At that time, I had a feeling of seeing through the clouds and seeing the light, thinking that this thing could continue to be done." Through further research, they found that these nanostructures could enter cells through endocytosis mediated by endocytosis and caveolin. Computer simulations indicate that these nanostructures are released in the form of dimers chelated by metal ions. The chelated dimer binds to a specific domain of the potassium ion channel, causing a phase transition in its overall structure, an increase in pore size, and a widening of the channel, thereby activating the potassium ion channel. With the outflow of potassium ions and inflow of calcium ions, a special signaling pathway regulated by calmodulin is activated, promoting dendritic cell maturation and triggering the secretion of pro-inflammatory cytokines. In addition, the research team found that nutritional restriction can enhance dendritic cell uptake of nanomaterials and further enhance pathway activity. Our experiments conducted at the small animal level found a significant improvement in the response rate to ICB treatment Wang Hai admitted, "Although the article has been published, there is still a gap between the research and clinical application. We are actively promoting it