肿瘤转移是造成癌症患者死亡的主要原因。中国科学院分子细胞科学卓越创新中心的王广川研究团 队联合相关合作团队建立了一种新型技术平台——CLIM-TIME，以小鼠为动物模型，揭示了肿瘤遗传 突变"改造"微环境进而导致免疫治疗耐药的基本规律。 王广川表示，研究首次在高通量（同时开展大规模分析）尺度上建立了"肿瘤内在遗传扰动-微环境 结构-免疫治疗效果"之间的因果联系。目前相关研究基于动物模型，临床场景更为复杂，需开展更多安 全性及疗效的评价。 0:00 / 3:56 肿瘤微环境导致免疫治疗耐药 科研人员破解其中密码 相关论文于北京时间12日在线发表于国际学术期刊《细胞》（Cell）。 近年来的研究发现，肿瘤微环境的特征和类型，与免疫治疗的效果密切相关。研究团队初步分析了 391种常见抑癌基因形成的转移瘤微环境如何影响免疫治疗，并将这些微环境分为七大类，对其中一类 进行了深入研究。 中国科学院分子细胞科学卓越创新中心研究员王广川当天在沪受访时介绍，团队深入研究的这一类 微环境里沉积了大量的胶原蛋白，微环境里的肿瘤细胞像蜘蛛，它们织了网，不仅给自身提供支撑， 还"猎捕"了更多免疫细胞，形成致密的屏障。这样的屏障，让免疫 ...

Core Insights - The study reveals that glucose metabolism is a critical energy source for tumor proliferation, and targeting glucose metabolism through low-carbohydrate diets is a promising strategy to inhibit tumor growth [2][9] - However, extreme carbohydrate restriction may suppress tumor growth while simultaneously promoting lung metastasis, indicating the need for careful evaluation of metabolic intervention strategies [3][9] Mechanism of Action - Glucose deprivation induces endoplasmic reticulum (ER) stress in tumor cells, activating HRD1 to catalyze the ubiquitination of TRAIL at the K63 site, which is then packaged into exosomes [4] - These exosomes release TRAIL in the lungs, polarizing PVR⁺ macrophages and depleting lung NK cells, thus creating a favorable immune microenvironment for tumor colonization [4] Clinical Implications - The research confirms that low glucose metabolism is associated with higher recurrence rates within two years post-surgery across 15 cancer types [5] - Plasma exosomal TRAIL levels serve as an effective biomarker for predicting lung metastasis after liver cancer surgery, outperforming traditional biomarkers like alpha-fetoprotein (AFP) [6] Key Findings - Low-carbohydrate diets or impaired glucose metabolism can promote lung metastasis [7] - Glucose deprivation creates a pre-metastatic microenvironment dominated by lung macrophages [7] - Exosomal TRAIL leads to the polarization of PVR⁺ macrophages, resulting in the depletion of lung NK cells [7] - Plasma exosomal TRAIL levels can accurately predict early postoperative lung metastasis [7] Research Value - The study systematically elucidates how glucose restriction reshapes distal immune environments and promotes tumor metastasis through an exosome-immune regulatory axis, highlighting the TIGIT pathway as a potential target for combined interventions [9]