Tianyi Tian, Siyu Zhao, Tian Tian, Wenjing Li, Zhenzhen Zhang, Tianzi Shi, Xiaonan Li, Xiong Liu, Hongbo Xu, Yuanyuan Guo, Boheng Zhang, Wei Jiang, Boning Niu, Zhiping Zhang
The limited effectiveness of chimeric antigen receptor macrophage (CAR-M) therapy is largely due to poor tumor infiltration, reduced effector function and immune escape of target antigen-low tumors. Here we developed syncytial CAR-Ms (S-CAR-M) by fusing CAR-Ms with neutrophils. S-CAR-Ms accumulated in tumors more than conventional CAR-Ms because of chemokine-driven migration. By releasing neutrophil extracellular traps and reactive oxygen species inherited from neutrophils, S-CAR-Ms increased PtdSer exposure on tumor cells, leading to efficient phagocytosis of tumor debris through both the scFv-antigen and PtdSer-MerTK pathways. Thus, a single dose of S-CAR-Ms can reduce tumor burden, limit metastasis and prevent tumor recurrence in syngeneic and xenograft mouse models. Additionally, S-CAR-M therapy triggered antigen spreading, minimizing escape by target antigen-low tumor cells. S-CAR-Ms overcome limitations of conventional CAR-Ms toward solid tumors.