Targeting AQP5-mediated arginine deprivation in gastric cancer stem cells restores NK cell anti-tumor immunity

Natural killer (NK) cells exhibit impaired anti-tumor activity upon entering the tumor microenvironment (TME); however, the precise mechanism(s) remains elusive. In this study, we demonstrate that AQP5(+) gastric cancer stem cells contribute to the dysfunction of NK cells by reprogramming the urea cycle (UC). Mechanistically, AQP5 competitively binds ATP-dependent RNA helicase A (DHX9) over karyopherin subunit beta 1 (KPNB1), inhibiting DHX9 nuclear translocation and transcriptionally down-regulating argininosuccinate synthase 1 (ASS1). Low-arginine condition in the TME reshaped by AQP5(+) tumor cells weakens NK cell function by limiting NO synthesis. Notably, preclinical murine models confirm that oral arginine supplements improve the NK cell-directed killing against organoids generated by AQP5(High) GC (gastric cancer) tissues. Besides, AQP5(+) tumor cells also redirect the UC to the TCA cycle, which stores the saved nitrogen in glutamine by promoting glutamate-ammonia ligase (GLUL) stability. This study uncovers the evidence of AQP5(+) cancer stem cells impairing NK cell cytotoxicity by changing self-metabolism patterns.