A research team led by Prof. WANG Yi and Prof. WEI Haiming from the University of Science and Technology of China (USTC) of the Chinese Academy of Sciences, together with Prof. DING Chen’s team from the Fudan University, revealed 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.

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. A previous study led by Prof. WANG’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, in this study, researchers investigated how high lactate levels in the bone marrow TME affect NK cell function. They identified that a high-lactate TME in the bone marrow induced Kla in NK cells, and that elevated Kla levels were strongly associated with impaired NAD⁺ homeostasis, mitochondrial fragmentation, and diminished anti-tumor activity.

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

Moreover, researchers revealed that the combination of these small molecules modulated the Kla level of the kinase ROCK1, which further influenced the phosphorylation status of the mitochondrial fission protein DRP1, thus preventing mitochondrial fragmentation and contributing to the restoration of NK cell function.

This study uncovers a new mechanism through which Kla impairs NK cell function, and 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.