肿瘤细胞治疗研究
英文原题：Programmable iPSC-derived CAR-NK vesicles remodel the immune microenvironment and eradicate tumors.
这些发现支持 CAR-iNEV 通过协同的肿瘤靶向和免疫微环境调控，在实体瘤中具有治疗潜力。
嵌合抗原受体（CAR）细胞疗法正在改变血液系统癌症治疗，但在实体瘤中的应用仍受基质屏障及免疫抑制性肿瘤微环境限制，导致免疫细胞浸润受阻。为应对这些障碍，研究者开发了一种无细胞治疗平台：由诱导多能干细胞（iPSC）来源自然杀伤（NK）细胞产生的CAR工程化细胞外囊泡（CAR-iNEV）。该平台保留肿瘤靶向能力，无需依赖活细胞递送。CAR-iNEV在多种异种移植及患者来源模型中显示强效抗肿瘤活性和良好耐受性。在机制上，CAR-iNEV直接清除肿瘤细胞，并通过促进促炎型巨噬细胞极化重塑肿瘤微环境，从而增强宿主先天抗肿瘤免疫。CAR-iNEV还可与免疫检查点阻断协同；联合CAR-iNEV和CD47抑制可增加肿瘤清除，并使存活小鼠产生长期免疫记忆。这些发现支持CAR-iNEV通过协同靶向肿瘤并调节免疫微环境治疗实体瘤的潜力。
Chimeric antigen receptor (CAR) cell therapy transforms hematologic cancer treatment but remains limited in solid tumors due to stromal barriers and an immunosuppressive tumor microenvironment that restricts immune cell infiltration. To address these barriers, we develop a cell-free therapeutic platform based on CAR-engineered induced pluripotent stem cell (iPSC)-derived natural killer (NK) extracellular vesicles (CAR-iNEVs), which retain tumor-targeting capability without reliance on live-cell delivery. CAR-iNEV demonstrates potent antitumor activity and excellent tolerability across multiple xenograft and patient-derived models. Mechanistically, CAR-iNEV directly eliminates tumor cells and remodels the tumor microenvironment by promoting pro-inflammatory macrophage polarization, thereby enhancing host innate antitumor immunity. CAR-iNEV also functions cooperatively with immune checkpoint blockade, and combined treatment with CAR-iNEV and CD47 inhibition increases tumor clearance and induces long-term immunological memory in surviving mice. These findings support the therapeutic potential of CAR-iNEV for solid tumors through coordinated tumor targeting and immune microenvironment modulation.
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