肿瘤细胞治疗研究
英文原题：A tumor-on-a-chip model reveals and targets reciprocal macrophage-NK cell crosstalk to advance immunotherapy screening.
A tumor-on-a-chip model reveals and targets reciprocal macrophage-NK cell crosstalk to advance immunotherapy screening.
有效的癌症免疫治疗受到肿瘤微环境中免疫抑制性串扰的阻碍。
有效的癌症免疫治疗受到肿瘤微环境内免疫抑制性串扰的阻碍。我们构建了一种肿瘤免疫微环境芯片（TIMoC），其再现了人实体肝肿瘤的血管化、缺氧和空间组织的生态位。我们利用TIMoC剖析了巨噬细胞与自然杀伤（NK）细胞之间的相互作用。巨噬细胞诱导NK细胞功能障碍，而功能失调的NK细胞促进M2巨噬细胞极化。这种双向损伤形成了一个自我延续的免疫抑制环路。TIMoC作为一种体外筛选工具，证实了TIGIT阻断在多细胞环境中的有限疗效，并揭示了巨噬细胞重编程剂（resiquimod）与NK细胞靶向抗体联合使用的协同抗肿瘤活性。通过整合患者来源的器官型肿瘤球体和自体免疫细胞，个性化TIMoC平台模拟了患者特异性反应并评估了有效的药物组合，展示了其指导精准免疫治疗的潜力。这项工作阐明了一个关键的免疫抑制轴，并引入了一个用于合理设计联合免疫治疗的多功能平台。
Effective cancer immunotherapy is hindered by immunosuppressive crosstalk within the tumor microenvironment. We engineered a tumor immune microenvironment-on-a-chip (TIMoC) that recapitulates the vascularized, hypoxic, and spatially organized niche of human solid liver tumors. We employed TIMoC to dissect the reciprocal interaction between macrophages and natural killer (NK) cells. Macrophages induced NK cell dysfunction, while dysfunctional NK cells promoted M2 macrophage polarization. This bidirectional impairment created a self-perpetuating immunosuppressive loop. TIMoC served as an in vitro screening tool, confirming the limited efficacy of TIGIT blockade in a multicellular context and revealing synergistic anti-tumor activity for combinations of a macrophage-reprogramming agent (resiquimod) with NK cell-targeting antibodies. By incorporating patient-derived organotypic tumor spheroids and autologous immune cells, the personalized TIMoC platform modeled patient-specific responses and evaluated effective drug combinations, demonstrating its potential to guide precision immunotherapy. This work elucidates a key immunosuppressive axis and introduces a versatile platform for rationally designing combination immunotherapies.
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