多细胞招募,免疫治疗 z-bio 2024-12-11 541

　　The biological orthogonal chimera targeting the immune microenvironment of solid tumors through "multicellular recruitment"

　　In the National Natural Science Foundation of China projects (approval numbers: 21432002, 21521003) T2288102、 Under the funding of 82150005, 32122035, 82274034, Professor Chen Peng from Peking University collaborated with Professor Xi Jianzhong, Professor Kang Xiaozheng from the Cancer Hospital of the Chinese Academy of Medical Sciences, Professor Li Yan from Nanjing University, and Researcher Lin Jian from the Third Hospital of Peking University to develop a "multicellular recruitment" bioorthogonal chimera that targets the immune microenvironment of solid tumors. The related achievement, titled "Multimodal targeting chimeras enable integrated immunotherapy leveraging tumor immune microenvironment," was published in Cell on November 5, 2024. The link to the paper is: https://www.cell.com/cell/abstract/S0092-8674 (24)01198-X。

　　Immunotherapy has brought revolutionary changes to cancer treatment, with most immunotherapies showing significant efficacy in hematological malignancies, but having low response rates and poor therapeutic effects in solid tumors. The main reason is that solid tumors have a complex and highly heterogeneous tumor immune microenvironment, and multiple types of immune cells work together to affect the effectiveness of immunotherapy. Under ideal conditions, developing therapeutic strategies that can simultaneously mobilize multiple immune cells will greatly improve the effectiveness of solid tumor treatment. However, traditional immune therapies such as immune checkpoint inhibitors, adoptive cell therapy, and bispecific/multispecific antibodies mostly only target a single type of immune cell. Therefore, it is urgent to develop a method that can simultaneously recruit multiple immune cells to fight against tumors.

　　In response to the above issues, the team has developed a highly modular bioorthogonal chimeric platform that utilizes its developed multispecific bioorthogonal coupling arm (T-Linker) to accurately integrate multiple drug molecules, thereby constructing various types of multispecific bioorthogonal chimeric (Multi TAC) for simultaneously recruiting T cells, dendritic cells (DC), natural killer cells (NK), and myeloid immune cells, targeting the immune microenvironment of solid tumors. The team systematically studied the EGFR-CD3-PDL1 Multi TAC chimera, which mediated the direct interaction between tumor cell-T cell-DC, activated T cells and DCs in tumor tissue, reversed the tumor immune microenvironment, induced tumor specific immune response, and ultimately significantly improved the efficacy of solid tumor immunotherapy. This study provides a new approach for tumor immunotherapy.