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

  • Cell Rep Med. 2025 Sep 16;6(9):102333. doi: 10.1016/j.xcrm.2025.102333.
Rou Zhao  1 ,  Baoyu He  2 ,  Lunhua Huang  3 ,  Yanli Wu  4 ,  Ting Liu  4 ,  Jilan Liu  2 ,  Mingsheng Zhao  5 ,  Tao Zhong  5 ,  Yanhua Zhang  6 ,  Xiao Zhang  7 ,  Huabao Xiong  8 ,  Bin Zhang  9 ,  Qingli Bie  10
Affiliations
  • 1. Key Laboratory of Cell and Biomedical Technology of Shandong Province, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China; Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China; Laboratory of Cancer Epigenetics, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China.
  • 2. Key Laboratory of Cell and Biomedical Technology of Shandong Province, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China; Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China.
  • 3. Department of Gastrointestinal Surgery, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China.
  • 4. Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China.
  • 5. Key Laboratory of Cell and Biomedical Technology of Shandong Province, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China; Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong 272067, China.
  • 6. Shanghai Cancer Center, Fudan University, Shanghai 200032, China.
  • 7. Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200032, China.
  • 8. Key Laboratory of Cell and Biomedical Technology of Shandong Province, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China; Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong 272067, China. Electronic address: [email protected].
  • 9. Key Laboratory of Cell and Biomedical Technology of Shandong Province, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China; Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China. Electronic address: [email protected].
  • 10. Key Laboratory of Cell and Biomedical Technology of Shandong Province, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China; Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China. Electronic address: [email protected].
PMID: 40961922 DOI: 10.1016/j.xcrm.2025.102333
Abstract

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 AQP5High 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.

Keywords
AQP5; NK cell; TCA cycle; cancer stem cell; urea cycle.
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