Gamma-butyrobetaine hydroxylase 1 confers metastatic advantage by shielding cancer cells from natural killer cell immunosurveillance

Primary tumors constantly shed cancer cells into the circulation, yet only a fraction of these cells manage to give rise to metastatic tumors. Success appears to depend on metabolic changes within metastatic tumor cells, but few details are known. Here we report that expression of the enzyme γ-butyrobetaine hydroxylase 1 (BBOX1) under the control of a super enhancer allows a subset of cells in various types of tumors to produce the metabolite cartinine, which inhibits the small GTPase RhoA in natural killer cells, preventing immunological synapse formation and thereby protecting the metastatic cells from destruction. Knocking down γ-butyrobetaine hydroxylase 1 in tumor cells promoted their destruction by natural killer cells in vitro and improved the efficacy of natural killer cell adoptive transfer therapy in vivo. These findings illustrate how a subpopulation of tumor cells hijacks the metabolite carnitine to evade immune surveillance in the tumor microenvironment. Targeting γ-butyrobetaine hydroxylase 1 may be a powerful anti-metastatic strategy.