RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
IL-21 对 NK 细胞的代谢再激活增强了针对 MHC I 类缺陷实体瘤的免疫治疗
英文原题：Metabolic reinvigoration of NK cells by IL-21 enhances immunotherapy against MHC class I-deficient solid tumors.
查看英文原题
Metabolic reinvigoration of NK cells by IL-21 enhances immunotherapy against MHC class I-deficient solid tumors.
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中文摘要
自然杀伤（NK）细胞是一种强效的细胞毒性淋巴细胞，对于通过丢失或下调主要组织相容性复合体I类（MHC class I）表达来逃逸T细胞介导免疫治疗的癌症，尤其具有治疗前景。
然而，敌意且免疫抑制性的肿瘤微环境（TME）极大地阻碍了肿瘤浸润NK细胞的功能，从而限制了治疗效果。在此，我们展示了一种白细胞介素21融合蛋白（IL-21-Fc），能够在体内安全有效地重编程NK细胞代谢并恢复其效应功能。IL-21-Fc与IL-15超激动剂（IL-15SA）或过继性NK细胞转移协同作用，在多种小鼠模型中根除MHC class I缺陷型肿瘤并赋予持久保护。在机制上，我们发现IL-21-Fc通过以乳酸脱氢酶A（LDHA）依赖的方式上调糖酵解来增强NK细胞效应功能。
本研究揭示了LDHA依赖性代谢重编程是NK细胞 rejuvenation 的关键轴，并将IL-21-Fc定位为一种有前景、可临床转化的策略，用以克服实体瘤中TME介导的免疫抑制。
展开英文摘要原文
Natural killer (NK) cells, a type of potent cytotoxic lymphocyte, are particularly promising for the treatment of cancers that lose or downregulate major histocompatibility complex class I (MHC class I) expression to evade T cell-mediated immunotherapy.
However, the hostile and immunosuppressive tumor microenvironment (TME) greatly hinders the function of tumor-infiltrating NK cells, thus limiting the therapeutic efficacy.
Here, we show a fusion protein of interleukin 21 (IL-21-Fc) that safely and effectively reprograms NK cell metabolism and restores their effector function in vivo. IL-21-Fc synergizes with IL-15 superagonist (IL-15SA) or adoptive NK cell transfer to eradicate MHC class I-deficient tumors and confer durable protection across multiple murine models.
Mechanistically, we uncover that IL-21-Fc enhances NK cell effector function by upregulating glycolysis in a lactate dehydrogenase A (LDHA)-dependent manner.
This study reveals LDHA-dependent metabolic reprogramming as a key axis for NK cell rejuvenation and positions IL-21-Fc as a promising, clinically translatable strategy to overcome TME-mediated suppression in solid tumors.
论文信息
- 作者
- Wang Y、Huang C、Cai G、Andreatta M、Kurum A、Zhao Y、Feng B、Gao M
- 第一作者单位
- Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; Institute of Materials Science & Engineering, EPFL, 1015 Lausanne, Switzerland.Switzerland
- 通讯作者单位
- Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; Institute of Materials Science & Engineering, EPFL, 1015 Lausanne, Switzerland. Electronic address: li.tang@epfl.ch.Switzerland
- 期刊
- Cell reports2026 Mar 24
- 原文标识
- PubMed 41758652 · DOI 10.1016/j.celrep.2026.117035