3D-printed implantable CAR-macrophages for post-surgery cancer immunotherapy

Chimeric antigen receptor macrophages (CAR-M) therapy holds significant clinical potential, while its application is severely compromised by poor in vivo colonization and limited persistence. Here, we report a 3D-printed implantable CAR-M (iCAR-M) system, composed of a gelatin methacrylate (GelMA) scaffold loaded with IL13Rα2-targeting CAR-M, and signal regulatory protein-α-overexpressing extracellular vesicles (SIRPα-EVs). Functioning as a bioactive reservoir, the porous hydrogel mitigates anoikis and promotes nutrient transport, markedly elevating CAR-M viability and increasing the frequency of activated macrophages in mice from ~ 5% to ~ 30% after 7 days. Mechanistically, the co-released SIRPα-EVs mask CD47 on tumor cells to abrogate the "don't eat me" signal, synergizing with CAR-mediated phagocytosis. In a 4T1 post-surgery model, this locoregional delivery system significantly inhibited tumor recurrence and remodeled the immunosuppressive microenvironment, boosting CD80⁺ macrophage polarization ~ 24% and CD8⁺ T-cell activation ~ 26%. Collectively, the iCAR-M functions as an engineered immune niche, integrating biomaterial-assisted persistence with checkpoint blockade to overcome solid tumor resistance.