肿瘤细胞治疗研究
英文原题：3D-printed implantable CAR-macrophages for post-surgery cancer immunotherapy.
iCAR-M 作为一种工程化免疫微环境，将生物材料辅助的持久性与检查点阻断相结合，以克服实体瘤耐药性。
嵌合抗原受体巨噬细胞（CAR-M）疗法具有显著的临床潜力，但其应用受到体内定植不良和持久性有限的严重制约。在此，我们报道了一种3D打印的可植入CAR-M（iCAR-M）系统，由负载靶向IL13Rα2的CAR-M的甲基丙烯酰化明胶（GelMA）支架和过表达信号调节蛋白α的细胞外囊泡（SIRPα-EVs）组成。作为一种生物活性储库，该多孔水凝胶可减轻失巢凋亡并促进营养运输，显著提高CAR-M的活力，并将小鼠体内活化巨噬细胞的比例在7天后从约5%提升至约30%。在机制上，共释放的SIRPα-EVs遮蔽肿瘤细胞上的CD47以消除“别吃我”信号，与CAR介导的吞噬作用协同增效。在4T1术后模型中，该局部递送系统显著抑制了肿瘤复发并重塑了免疫抑制微环境，使CD80⁺巨噬细胞极化提升约24%，CD8⁺T细胞活化提升约26%。总体而言，iCAR-M作为一种工程化免疫生态位，将生物材料辅助的持久性与检查点阻断相结合，以克服实体瘤耐药。
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.
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