Mannose-binding lectin 2 secreted by hepatocellular carcinoma cells recruits and activates natural killer cells to reshape an immune-activated microenvironment.

Crosstalk between hepatocellular carcinoma (HCC) and the tumor microenvironment (TME) is pivotal for the initiation and management of HCC. The infiltration and function of natural killer (NK) cells in the TME are frequently hindered. However, it is unclear whether a crucial regulatory factor originating from HCC cells directly modulates NK cell activity to evade immune surveillance. In this study, we found that mannose-binding lectin 2 (MBL2) expression was markedly decreased in HCC and positively correlated with HCC prognosis. MBL2 inhibited the proliferation and migration of HCC cells intracellularly. Human and murine co-culture systems of HCC and NK cells were established to demonstrate that secreted MBL2 recruited and activated NK cells in the TME, particularly upregulating the infiltration of NKp46+ NK cells. Furthermore, secreted MBL2 promoted the production of IL-13 and IL-25 by NK cells, resulting in a decrease in exhausted cytotoxic T lymphocytes. Mechanistically, MBL2 interacts with the integrin β1 receptor, activating the FAK/AKT pathway and increasing PD-L1 expression on NK cells. Our discovery identifies MBL2 as an NK cell-activating cytokine, initiating the integrin β1/FAK/AKT pathway in NK cells and reshaping an immune-activated microenvironment of HCC. Strategies to up-regulate MBL2 may enhance the anti-PD-L1 immunotherapy efficacy and serve as a potential therapeutic approach for HCC.