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

Rou Zhao; Baoyu He; Lunhua Huang; Yanli Wu; Ting Liu; Jilan Liu; Mingsheng Zhao; Tao Zhong; Yanhua Zhang; Xiao Zhang; Huabao Xiong; Bin Zhang; Qingli Bie

doi:10.1016/j.xcrm.2025.102333

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.

Authors

Rou Zhao¹, Baoyu He², Lunhua Huang³, Yanli Wu⁴, Ting Liu⁴, Jilan Liu², Mingsheng Zhao⁵, Tao Zhong⁵, Yanhua Zhang⁶, Xiao Zhang⁷, Huabao Xiong⁸, Bin Zhang⁹, Qingli Bie¹⁰

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.

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 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.

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

MeSH terms

Animals
Aquaporin 5* / metabolism
Arginine* / deficiency
Arginine* / metabolism
Cell Line, Tumor
Humans
Killer Cells, Natural* / immunology
Killer Cells, Natural* / metabolism
Mice
Neoplastic Stem Cells* / immunology
Neoplastic Stem Cells* / metabolism
Neoplastic Stem Cells* / pathology
Stomach Neoplasms* / immunology
Stomach Neoplasms* / metabolism
Stomach Neoplasms* / pathology
Tumor Microenvironment
Urea / metabolism

Substances

Arginine
Aquaporin 5
AQP5 protein, human
Urea