2. Academic Validation
  3. Targeting AQP5-mediated arginine deprivation in gastric cancer stem cells restores NK cell anti-tumor immunity

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

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: xionghbl@163.com.
  • 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: zhangbin@mail.jnmc.edu.cn.
  • 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: xiaobie890101@163.com.
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.

Figures
Products