肿瘤细胞治疗研究
英文原题：In Situ Chimeric Antigen Receptor Macrophage Therapy via Co-Delivery of mRNA and Immunostimulant.
我们的发现提出了一种基于LNP的CAR-巨噬细胞免疫治疗方法，以克服传统CAR-T细胞疗法的局限性。
利用嵌合抗原受体（CAR）技术的肿瘤免疫治疗在血液系统恶性肿瘤中取得了显著的临床成功，但在实体瘤中面临局限。在替代策略中，CAR-巨噬细胞治疗在实体瘤环境中具有独特优势。然而，目前的体外方法受到巨噬细胞基因转移效率低下以及维持抗肿瘤巨噬细胞表型困难的阻碍。在此，我们报道了一种通过共递送mRNA和免疫刺激剂实现的原位CAR-巨噬细胞治疗。通过利用设计用于选择性转染肿瘤相关巨噬细胞的脂质纳米颗粒（LNP），我们规避了大量体外操作，并直接在肿瘤微环境内实现稳健的CAR表达。此外，共递送干扰素基因刺激因子（STING）激动剂可放大局部免疫激活，从而在小鼠黑色素瘤模型中增强CAR-巨噬细胞功能并提升抗肿瘤效果。这种体内策略通过实现直接细胞靶向、强效免疫调节和简化制造，解决了CAR-巨噬细胞治疗在实体瘤中的关键障碍。我们的发现提出了一种基于LNP的CAR-巨噬细胞免疫治疗方法，以克服传统CAR-T细胞治疗相关的局限性。
Cancer immunotherapy employing chimeric antigen receptor (CAR) technology has achieved significant clinical success in hematologic malignancies, but faces limitations in solid tumors. Among alternative strategies, CAR-macrophage therapy offers distinct advantages in solid tumor settings. However, current ex vivo approaches are hindered by inefficient gene transfer into macrophages and challenges in maintaining an antitumor macrophage phenotype. Here, we report an in situ CAR-macrophage therapy via codelivery of mRNA and immunostimulant. By leveraging lipid nanoparticles (LNPs) designed to selectively transfect tumor-associated macrophages, we circumvent extensive ex vivo manipulation and achieve robust CAR expression directly within the tumor microenvironment. Furthermore, codelivery of a stimulator of interferon genes (STING) agonist amplifies local immune activation, leading to reinforced CAR-macrophage functionality and enhanced antitumor effects in a mouse melanoma model. This in vivo strategy addressed key obstacles of CAR-macrophage therapy in solid tumors by enabling direct cellular targeting, potent immunomodulation, and simplified manufacturing. Our findings suggest an LNP-enabled approach for CAR-macrophage immunotherapy to overcome the limitations associated with conventional CAR-T cell therapies.
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