Neutral sphingomyelinases restrict natural killer cells activity against lung cancer.

High frequency and activity of tumor-infiltrating natural killer (NK) cell is associated with improved prognosis in several solid cancers including non-small cell lung cancer. However, multiple factors can suppress NK cell activity within the tumor microenvironment, resulting in impaired killing of tumor cells. For NK cells to engage and kill target cells, stabilization of lipid rafts is essential. Sphingomyelin is involved in lipid raft formation and is catabolized by sphingomyelinases. While inhibition of sphingomyelinases enhances NK cell-mediated killing of tumor cells, it is unknown how sphingomyelinases impact on the ability of NK cells to infiltrate solid tumors. Here we demonstrate that inhibition of sphingomyelinases results in increased activation and ability of NK cells to infiltrate lung adenocarcinoma. Overall, our findings support the use of sphingomyelinase inhibitors as enhancers of NK cell activation.