Molecular mechanism of S100A11 inhibiting anti-HCC immune function of NK cells

Objective To explore the regulatory role and underlying molecular mechanism of S100A11 in the anti-hepatocellular carcinoma (HCC) function of natural killer (NK) cells, and to provide a novel target and theoretical basis for optimizing immunotherapy for HCC. Methods The expression of S100A11 was validated in clinical specimens. A stable S100A11 -knockdown NK92 cell line was established via lentiviral transfection. CCK-8 assay, cell cytotoxicity assay, flow cytometry, Western blot and other experiments were performed to detect changes in NK cell biological functions and related signaling pathways. An HCC xenograft mouse model was established to verify the antitumor effect in vivo. Results S100A11 was highly expressed in HCC tissues, and its expression level was positively correlated with pathological differentiation grade. Knockdown of S100A11 significantly enhanced the proliferation, degranulation, cytokine secretion and cytotoxic activity of NK92 cells against HCC cells. Moreover, S100A11 knockdown upregulated the expression of activating receptors and downregulated inhibitory receptors on the surface of NK cells. Mechanistically, S100A11 regulated NK cell functions by suppressing the phosphorylation of key molecules in the MAPK signaling pathway and the endoplasmic reticulum stress pathway. In vivo experiments demonstrated that S100A11 -knockdown NK92 cells markedly restrained tumor growth, increased NK cell infiltration in tumor tissues, and caused no obvious hepatic injury. Conclusion S100A11 inhibits the anti-HCC immune function of NK cells by negatively regulating the MAPK and endoplasmic reticulum stress signaling pathways. Targeting S100A11 can restore the cytotoxic activity of NK cells, which is expected to serve as a novel potential target for precise immunotherapy of HCC.