A research team led by Prof. WANG Yi and WEI Haiming from the University of Science and Technology of China (USTC), in collaboration with Prof. DING Chen’s team from Human Phenome Institute at Fudan University, has elucidated the role of lactate-induced lysine lactylation (Kla) in modulating Natural Killer (NK) cell anti-tumor responses within the tumor microenvironment (TME). The study was published in Nature Immunology on June 10.

NK cells play a pivotal role in cancer immunotherapy due to their rapid immune response, broad-spectrum anti-tumor activity, high versatility, and low toxicity. However, this potent anti-tumor capability can be compromised by TME, which produces various metabolites, including lactate. Although lactate’s inhibitory effect on NK cells has been observed, the underlying mechanism remains unclear. One such study, led by Prof. WANG Yi’s team, proposed an in vivo strategy targeting Kla in hepatocellular carcinoma (HCC), suggesting that lactate might impair NK cell function by promoting Kla.

To further elucidate this mechanism, the current study investigated how high lactate levels in the bone marrow TME affect NK cell function. The researchers identified that a high-lactate TME in the bone marrow induced Kla in NK cells. Elevated Kla levels were, in turn, strongly associated with impaired NAD⁺ homeostasis, mitochondrial fragmentation, and diminished anti-tumor activity.

Building on previous research on enhancing NK cell anti-tumor activity with small molecules, researchers proposed a new intervention strategy in this study. They supplemented nicotinamide riboside (a precursor of NAD⁺) with honokiol (a SIRT3 activator) to boost the activity of SIRT3 (an enzyme that removes Kla). This approach helped reduce Kla levels and restore the anti-tumor function of NK cells.

Mechanistically, they clarified that the combination of these small molecules modulated the Kla level of the kinase ROCK1. This, in turn, influenced the phosphorylation status of the mitochondrial fission protein DRP1, ultimately preventing mitochondrial fragmentation and contributing to the restoration of NK cell function.

Schematic of lactate-induced Kla impairing NK cell function and its reversal via SIRT3 activation. (Image from Prof. WANG’s team)

This study, by uncovering a new mechanism through which Kla impairs NK cell function, offers a novel theoretical framework for restoring NK cell-mediated anti-tumor immunity in TME. It also provides a promising strategy to enhance the efficacy of NK cell-based immunotherapy.

Paper link: https://doi.org/10.1038/s41590-025-02178-8

(Written by SHEN Xinyi, Edited by Wu Yuyang, USTC News Center)