Targeting palmitoylation enhances neutrophil-mediated cancer cell killing in liver metastases [RNA-seq]

Liver metastases are frequent and challenging to treat as the liver is a metabolically highly active and immune-tolerant organ. However, how cancer cells exploit the nutrients available in the liver to further exacerbate evasion from the immune system remains largely unknown. We discovered that palmitate availability in the liver promotes neutrophil extracellular traps (NETs) in the presence of cancer cells. Mechanistically, we found that liver metastases from breast and colorectal cancer require the palmitoyltransferase 17 (DHHC17, gene name ZDHHC17) to secrete laminin-511. In turn, neutrophils in the liver metastasis environment responded to laminin-511 by increasing NETosis and decreasing their cancer cell killing capacity. In line, we observed that silencing ZDHHC17 in cancer cells decreased metastasis growth only in the presence of neutrophils, while metastasis growth was rescued in ZDHHC17-silenced metastases upon injection of laminin-511 or inhibition of neutrophil degranulation. Taken together, we found that liver palmitate not only aids cancer cell intrinsic processes but it also enables cancer cells to evade neutrophil destruction.