Jing Jin, Peidong Yan, Dongyao Wang, Lin Bai, Hao Liang, Xiaoyu Zhu, Huaiping Zhu, Chen Ding, Haiming Wei, Yi Wang
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引用次数: 0
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.
期刊介绍：
Nature Immunology is a monthly journal that publishes the highest quality research in all areas of immunology. The editorial decisions are made by a team of full-time professional editors. The journal prioritizes work that provides translational and/or fundamental insight into the workings of the immune system. It covers a wide range of topics including innate immunity and inflammation, development, immune receptors, signaling and apoptosis, antigen presentation, gene regulation and recombination, cellular and systemic immunity, vaccines, immune tolerance, autoimmunity, tumor immunology, and microbial immunopathology. In addition to publishing significant original research, Nature Immunology also includes comments, News and Views, research highlights, matters arising from readers, and reviews of the literature. The journal serves as a major conduit of top-quality information for the immunology community.
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