中国科学技术大学王毅小组的论文发现了靶向乳酸化增强NK细胞在肿瘤微环境中的细胞毒性。相关论文于2025年6月10日发表于国际顶尖学术期刊《自然—免疫学》杂志上。

在这里，该课题组人员发现NK细胞中Kla水平的增加伴随着烟酰胺腺嘌呤二核苷酸代谢受损、线粒体碎片化和细胞毒性降低。补充烟酰胺核苷（烟酰胺腺嘌呤二核苷酸前体）和檀香醇（SIRT3激活剂）通过降低细胞Kla水平增强NK细胞的细胞毒性。该组合通过调节ROCK1上的Kla，从而抑制ROCK1-DRP1信号传导以防止线粒体断裂，从而恢复NK细胞体内和体外的抗白血病活性。总之，本研究显示了乳酸化如何损害NK细胞，并强调了这种乳酸化是NK细胞免疫治疗的靶标，以增强肿瘤微环境中对乳酸的恢复能力。

据介绍，自然杀伤（NK）细胞的功能障碍可能与肿瘤微环境中肿瘤来源的乳酸有关。乳酸诱导的赖氨酸乳酸化（Kla）是一种翻译后修饰，旨在增强NK细胞对Kla的抗性的策略可能会增强细胞毒性。

附：英文原文

Title: Targeting lactylation reinforces NK cell cytotoxicity within the tumor microenvironment

Author: Jin, Jing, Yan, Peidong, Wang, Dongyao, Bai, Lin, Liang, Hao, Zhu, Xiaoyu, Zhu, Huaiping, Ding, Chen, Wei, Haiming, Wang, Yi

Issue&Volume: 2025-06-10

Abstract: Dysfunction of natural killer (NK) cells can be associated with tumor-derived lactate in the tumor microenvironment. Lactate-induced lysine lactylation (Kla) is a posttranslational modification, and strategies aimed at augmenting NK cell resistance to Kla might enhance cytotoxicity. Here we show that increased Kla levels in NK cells are accompanied by impaired nicotinamide adenine dinucleotide metabolism, fragmented mitochondria and reduced cytotoxicity. Supplementation with nicotinamide riboside (a nicotinamide adenine dinucleotide precursor) and honokiol (a SIRT3 activator) enhanced NK cell cytotoxicity by reducing cellular Kla levels. This combination restores antileukemic activity of NK cells in vivo and ex vivo by modulating Kla on ROCK1, thereby inhibiting ROCK1–DRP1 signaling to prevent mitochondrial fragmentation. Altogether, this study shows how lactylation can compromise NK cells and highlights this lactylation as a target for NK cell-based immunotherapy to enhance resilience to lactate in the tumor microenvironment.

DOI: 10.1038/s41590-025-02178-8

Source: https://www.nature.com/articles/s41590-025-02178-8