BBOX1 is a Metabolic Checkpoint that Mediates Metastatic Cancer Cell Evasion from Immunosurveillance by Natural Killer Cells

Abstract Primary tumors constantly shed cancer cells into the circulation, yet only a fraction of these cells manages to give rise to metastatic tumors. Successful metastatic seeding and growth appears to depend on metabolic changes within cancer cells. Here, using a metabolism-focused CRISPR screen in a spontaneous metastasis model, we found that expression of the enzyme γ-butyrobetaine hydroxylase 1 (BBOX1) in a subpopulation of tumor cells in various carcinomas enables immune evasion. The metabolite carnitine produced by BBOX1 inhibited the small GTPase RhoA in natural killer (NK) cells, preventing immunological synapse formation and thereby protecting metastatic cells. Loss of BBOX1 in tumor cells promoted their destruction by NK cells in vitro and improved the efficacy of NK cell adoptive transfer therapy in vivo. These findings illustrate how BBOX1-positive tumor cells hijack carnitine production to evade immune surveillance during metastasis and propose BBOX1 as a potential metabolic checkpoint for anti-metastatic strategies.