With the development of medical technology, immunotherapy represented by CAR-T therapy has attracted increasing attention from scholars and brought good news to cancer patients. Compared with CAR-T therapy, CAR-M therapy, which also introduces chimeric antigen receptors (CARs) to enable immune cells to precisely attack tumor cells, is an emerging and less well-known approach. Recently, Professor Shi Yu's team from Southwest Hospital of Army Medical University published a review article titled "Using Chimeric Antigen Receptor Macrophages to Combat Solid Tumors" in the journal Cancer Communications, systematically explaining the breakthrough mechanism of CAR-M therapy and exploring the latest progress and clinical translation challenges of this emerging therapy in the field of solid tumor treatment. CAR-M therapy, also known as chimeric antigen receptor macrophage therapy, is an emerging cancer immunotherapy approach that reduces damage while delivering precise strikes. ”Shi Yu introduced that, in simple terms, its core idea is to extract macrophages from the patient's body - immune cells that can naturally "eat" harmful substances and tumor cells, and then install "precision navigation devices" chimeric antigen receptors on them in the laboratory. Then, these chimeric antigen receptor macrophages are infused back into the patient's body, allowing them to recognize and attack tumor cells. Chimeric antigen receptor macrophages also play the role of "intelligence agents", presenting processed tumor antigen information to T cells (a type of immune cell) and releasing cytokines that promote immune responses, effectively improving the tumor microenvironment and creating favorable conditions for more immune cells to accurately attack tumor cells. Shi Yu told reporters that in addition to improving the tumor microenvironment, CAR-M therapy also has the following advantages. Firstly, due to the ability of chimeric antigen receptor macrophages to sense the 'signals' emitted by tumor cells, they can more accurately locate tumor cells and strike them with precision. Secondly, chimeric antigen receptor macrophages have a relatively low risk of causing severe cytokine release syndrome (i.e. an overly intense immune response), with fewer side effects and higher safety. They can strike tumor cells with precision while reducing harm to the human body, "said Shi Yu. Although CAR-M and CAR-T therapies are similar in principle, they each have their own unique ways of attacking tumors. ”Shi Yu said that CAR-T therapy mainly precisely "kills" tumor cells through cytotoxic effects, while CAR-M therapy "eats" tumor cells by infiltrating solid tumor tissue. Through in-depth research to compensate for technical deficiencies, it has been learned that although CAR-M therapy has many advantages, clinical and preclinical studies have also shown that the application of this therapy in clinical practice is not only limited by difficulties in obtaining, cultivating, and scaling up chimeric antigen receptor macrophages, but also by factors such as unclear survival time of chimeric antigen receptor macrophages in tumor tissues and unclear risk of "assimilation". At present, in response to the limitations of CAR-M therapy, domestic and foreign research teams have made significant progress in the design of chimeric antigen receptor structures, expansion of cell sources, and gene editing to enhance cell function. ”Shi Yu said that these developments are also included in the review article published this time. For example, a research team has integrated two functional signaling domains into chimeric antigen receptors, allowing chimeric antigen receptor macrophages to not only more effectively engulf tumor cells after recognizing tumors, but also release large amounts of pro-inflammatory cytokines such as IL-12 and IFN - γ, awakening and activating other immune cells in the body to jointly attack tumors, thereby significantly improving anti-tumor efficacy. Some researchers have also found new sources of chimeric antigen receptor macrophages. ”Shi Yu introduced that domestic and foreign research teams such as the Hematology Hospital of the Chinese Academy of Medical Sciences (Institute of Hematology) have successfully used human pluripotent stem cells to culture and prepare chimeric antigen receptor macrophages on a large scale in vitro. This method solves the problems of limited primary macrophages, difficulty in amplification, and low gene editing efficiency. In addition, Shi Yu introduced that some researchers are also exploring the direct use of macrophages in patients' bodies as a source of chimeric antigen receptor macrophages. The research team of Shandong University Affiliated Qilu Hospital and others designed precise targeted nanocarriers to directly deliver genes to these macrophages in the body, which can be transformed into chimeric antigen receptor macrophages in situ, eliminating the tedious in vitro cell preparation process. At the same time, in order to further enhance the "combat effectiveness" of chimeric antigen receptor macrophages, scientists also used gene editing technology to optimize the chimeric antigen receptor macrophages themselves, thereby enhancing their anti-tumor ability. Through these improvements, some limitations of CAR-M therapy have been effectively addressed. The results of the world's first CAR-M therapy clinical trial announced earlier this year showed that none of the 14 patients treated with chimeric antigen receptor macrophages developed severe cytokine release syndrome. Four patients remained stable after treatment, and the number of T cells in peripheral blood and tumor microenvironment increased to some extent. This indicates that CAR-M therapy does help activate and reshape anti-tumor immune responses, bringing new hope to cancer patients. ”Professor Ping Yifang from the Pathology Department of Southwest Hospital of Army Medical University said. Clinical translation requires multi therapy collaboration. With the release of the clinical trial results of CAR-M therapy, the clinical translation of this therapy has also been put on the agenda. So, how can CAR-M therapy be better applied in clinical practice? The research team found in related explorations that synergistic cooperation with existing mature treatment methods is one of the key directions to solve this problem. In our article, we clearly pointed out that chemotherapy, radiotherapy, or targeted drugs can destroy tumor cells and release more signals, which can actually enhance the phagocytic ability, antigen presentation ability, and immune activation ability of chimeric antigen receptor macrophages. Shi Yu said that in the future, CAR-M therapy will still rely on the support of chemotherapy and radiotherapy. In addition, research results have shown that the combination of chimeric antigen receptor macrophages and immune checkpoint inhibitors in immunotherapy can more effectively stimulate the body's anti-tumor immune response and further enhance therapeutic efficacy. Therefore, how to better integrate existing therapies in clinical practice is the next direction that researchers need to strive for. Shi Yu emphasized that chimeric antigen receptor macrophages also show broad prospects in the treatment of non tumor diseases. Macrophages are core members of innate immunity, not only capable of anti-tumor effects, but also involved in the occurrence and development of various non tumor diseases such as infections, fibrosis, neurodegenerative diseases, and inflammatory diseases. Compared to tumors, the targets of these non tumor diseases are usually more stable, the burden of lesions is lighter, and the immunosuppressive microenvironment is weaker, so the challenges faced by CAR-M therapy may be smaller. Research has shown that CAR-M therapy has achieved positive results in these non tumor fields. ”He said. Although CAR-M therapy has shown great potential in the field of oncology and has made significant progress in clinical translation, there is still a long way to go before it can be truly used in clinical practice. ”Shi Yu said that in the next step, the team will focus on in-depth analysis of the interaction network between chimeric antigen receptor macrophages and other immune cells, building a more effective immune stimulation microenvironment, exploring the establishment of a biomarker system based on liquid biopsy, real-time evaluation of efficacy, and optimization of drug delivery plans. The team will actively conduct research to enable CAR-M therapy to be applied more quickly in clinical practice and benefit patients. (New Society)