Neutrophil-integrated syncytial CAR macrophage for cancer immunotherapy

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.