Metabolic reprogramming of liver-resident NK Cells by IL-37a promotes hepatocellular carcinoma progression 2940

Abstract Description Interleukin-37 (IL-37), a newly identified cytokine of the IL-1 family, has emerged as a key regulator of inflammation and carcinogenesis. However, the specific role of the IL-37a isoform in hepatocellular carcinoma (HCC) development remains poorly understood. In this study, we found that IL-37a promotes HCC progression through an NK cell-dependent mechanism. Specifically, IL-37a modulates the distribution and function of liver-resident NK (LrNK) cells within the tumor microenvironment. Mechanistically, IL-37a orchestrates lipid metabolism in tumor cells, leading to aberrant lipid secretion. This secretion induces intracellular lipid accumulation in LrNK cells, resulting in impaired effector functions. Furthermore, we identified a distinct LrNK subset characterized by elevated lipid accumulation, signifying a shift from pro-inflammatory to anti-inflammatory phenotypes. We further constructed a human NK cell atlas and observed similar functional defects in NK cells from HCC patients. Metabolic analysis revealed that lipid peroxidation impaired glycolysis in LrNK cells. Importantly, treatment with MAPK agonist partially restored LrNK cell function, demonstrating the therapeutic potential of targeting metabolic pathways in HCC. In summary, our study provided critical insights into the complex interplay of cytokines within the tumor microenvironment, offering potential avenues for therapeutic intervention. Funding Sources Supported by National Research Foundation, Singapore (NRF-CRP26-2021RS-0001); Topic Categories Cytokines and Chemokines and Their Receptors (CCR)