肿瘤细胞治疗研究
英文原题：SynNotch-iNOS CAR-macrophages remodel the tumor immune microenvironment and exhibit antitumor efficacy via a CD4(+) T cell-dependent mechanism.
本研究阐明了一种 CAR-M 的新型间接机制，将关注点从直接吞噬转向策略性的 TIME 重塑，为治疗实体瘤提供了基础。
背景：CAR-T 细胞疗法治疗实体瘤的疗效有限，原因是免疫抑制性肿瘤微环境（TME）。巨噬细胞具有优异的浸润能力，但其治疗潜力尚未充分发挥。 方法：我们构建了一种synNotch-iNOS CAR巨噬细胞（CAR iNOS-M），在识别CD19后释放一氧化氮（NO）。在同基因背景、免疫功能完整的转移性黑色素瘤小鼠模型中评估其疗效。 结果：CAR iNOS-M治疗有效重编程肺部肿瘤免疫微环境（TIME），诱导强效抗肿瘤应答；该作用不依赖CD8⁺ T细胞，但严格依赖CD4⁺ T细胞。从机制上看，CAR iNOS-M治疗显著减少促肿瘤肺间质巨噬细胞，继而降低血小板因子4（PF4）水平。对PF4信号轴的破坏抑制了免疫抑制性Th1-Treg极化，从而减轻T细胞耗竭。 结论：本研究阐明CAR-M的一种新型间接作用机制，将关注点由直接吞噬转向策略性重塑TIME，为治疗实体瘤提供了依据。
BACKGROUND: Chimeric antigen receptor T-cell (CAR-T) therapy shows limited efficacy against solid tumors due to the immunosuppressive tumor microenvironment (TME). Macrophages possess superior infiltration capabilities, yet their therapeutic potential remains under-realized. METHODS: We engineered a synNotch-iNOS CAR-macrophage (CAR iNOS-M) that releases nitric oxide (NO) upon CD19 recognition. Its efficacy was evaluated in syngeneic, immunocompetent murine models of metastatic melanoma. RESULTS: CAR iNOS-M therapy effectively reprogrammed the pulmonary tumor immune microenvironment (TIME), inducing potent antitumor responses independent of CD8 + T cells but strictly dependent on CD4 + T cells. Mechanistically, CAR iNOS-M treatment led to a significant reduction in pro-tumorigenic lung interstitial macrophages (IMs), subsequently decreasing platelet factor 4 (PF4) levels. This disruption of the PF4 signaling axis inhibited the polarization of immunosuppressive Th1-Tregs, alleviating T-cell exhaustion. CONCLUSIONS: This study delineates a novel indirect mechanism for CAR-M, shifting the focus from direct phagocytosis to strategic TIME remodeling, providing a foundation for treating solid tumors.
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