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 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.