METTL7A Downregulation Drives SLC1A5‐Mediated Glutamine Competition to Promote Tumor Proliferation and Suppress CD8+ T Cell Immunity in Gastric Cancer
10 affiliations
- 1Department of General Surgery The Fourth Affiliated Hospital of Harbin Medical University Harbin China
- 2Heilongjiang Provincial Key Laboratory of Gastrointestinal Surgery and Nutrition Metabolism Harbin China
- 3Future Medical Laboratory The Second Affiliated Hospital of Harbin Medical University Harbin China
- 4Department of Vascular Surgery The First Affiliated Hospital of Fujian Medical University Fuzhou China
- 5Department of Vascular Surgery National Regional Medical Center Binhai Campus of the First Affiliated Hospital Fujian Medical University Fuzhou China
- 6College of Life Science and Agriculture Forestry Qiqihar University Qiqihar China
- 7Department of General Surgery Harbin Fourth Hospital Harbin China
- 8Department of Pharmacology College of Pharmacy Harbin Medical University Harbin China
- 9Department of Inorganic Chemistry and Physical Chemistry College of Pharmacy Harbin Medical University Harbin China
- 10State Key Laboratory of Neurology and Oncology Drug Development Nanjing China
Abstract
Tumor metabolic dysregulation is a critical determinant of tumor progression and response to immunotherapy. Aberrant glutamine metabolism is a hallmark of gastric cancer (GC). However, beyond fueling GC cell anabolism, its role in remodeling the immunosuppressive tumor microenvironment remains poorly understood. Here, we show that GC cells overexpress solute carrier family 1 member 5 (SLC1A5) to drive glutamine accumulation, which not only promotes their own proliferation but also reduces glutamine availability to CD8+ T cells, thereby suppressing antitumor immunity. These dual effects cooperatively drive GC progression. Mechanistically, loss of methyltransferase‐like protein 7A (METTL7A) stabilizes SLC1A5 mRNA by reducing its m6A modification. Concurrently, METTL7A deficiency increased N‐glycosyltransferase β‐1,4‐galactosyltransferase 5 (B4GALT5) expression. B4GALT5 stabilizes SLC1A5 via N‐glycosylation at the N212 site, which blocks K48‐linked polyubiquitination and proteasomal degradation. We identify the natural flavonoid luteolin as an agent that upregulates METTL7A expression, which subsequently downregulates SLC1A5 expression and inhibits GC progression. Furthermore, luteolin significantly enhances the efficacy of anti‐PD‐1 therapy in GC. Collectively, our findings reveal that SLC1A5‐mediated glutamine competition drives both tumor cell proliferation and immune evasion in GC, and suggest that targeting the METTL7A/SLC1A5 axis may represent a promising therapeutic strategy.
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BibTeX
@article{sun2026mettl7a,
title = {{METTL7A Downregulation Drives SLC1A5‐Mediated Glutamine Competition to Promote Tumor Proliferation and Suppress CD8+ T Cell Immunity in Gastric Cancer}},
author = {Mingjun Sun and Shuwei Dang and Dazhi Zhou and Lixian Ding and Xun Sun and Wei Suo and Jirui Niu and Qingzhu Yang and Zhicheng Zhang and Yanyan Sun and Jinxing Li and Zhongsheng Chen and Tao Ban and Yingji Wang and Tianzhu Li and Ming Liu and Guodong Li},
journal = {Advanced Science},
year = {2026},
month = aug,
doi = {10.1002/advs.76963},
url = {https://doi.org/10.1002/advs.76963},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - METTL7A Downregulation Drives SLC1A5‐Mediated Glutamine Competition to Promote Tumor Proliferation and Suppress CD8+ T Cell Immunity in Gastric Cancer
AU - Mingjun Sun
AU - Shuwei Dang
AU - Dazhi Zhou
AU - Lixian Ding
AU - Xun Sun
AU - Wei Suo
AU - Jirui Niu
AU - Qingzhu Yang
AU - Zhicheng Zhang
AU - Yanyan Sun
AU - Jinxing Li
AU - Zhongsheng Chen
AU - Tao Ban
AU - Yingji Wang
AU - Tianzhu Li
AU - Ming Liu
AU - Guodong Li
PY - 2026
DA - 2026/08/03
JO - Advanced Science
DO - 10.1002/advs.76963
UR - https://doi.org/10.1002/advs.76963
AB - Tumor metabolic dysregulation is a critical determinant of tumor progression and response to immunotherapy. Aberrant glutamine metabolism is a hallmark of gastric cancer (GC). However, beyond fueling GC cell anabolism, its role in remodeling the immunosuppressive tumor microenvironment remains poorly understood. Here, we show that GC cells overexpress solute carrier family 1 member 5 (SLC1A5) to drive glutamine accumulation, which not only promotes their own proliferation but also reduces glutamine availability to CD8+ T cells, thereby suppressing antitumor immunity. These dual effects cooperatively drive GC progression. Mechanistically, loss of methyltransferase‐like protein 7A (METTL7A) stabilizes SLC1A5 mRNA by reducing its m6A modification. Concurrently, METTL7A deficiency increased N‐glycosyltransferase β‐1,4‐galactosyltransferase 5 (B4GALT5) expression. B4GALT5 stabilizes SLC1A5 via N‐glycosylation at the N212 site, which blocks K48‐linked polyubiquitination and proteasomal degradation. We identify the natural flavonoid luteolin as an agent that upregulates METTL7A expression, which subsequently downregulates SLC1A5 expression and inhibits GC progression. Furthermore, luteolin significantly enhances the efficacy of anti‐PD‐1 therapy in GC. Collectively, our findings reveal that SLC1A5‐mediated glutamine competition drives both tumor cell proliferation and immune evasion in GC, and suggest that targeting the METTL7A/SLC1A5 axis may represent a promising therapeutic strategy.
SN - 2198-3844
ER -