In vivo CRISPR screens identify the glutamine transporter SLC1A5 as a metabolic barrier to antitumor immunity
Tumor cells often evade immune pressure via metabolic reprogramming, yet the key metabolic regulators orchestrating this process remain incompletely defined. Here, using in vivo metabolic CRISPR screening under distinct immune pressures, we identified tumor cell-intrinsic solute carrier family 1 member 5 (SLC1A5) as a metabolic node that sustains an immunosuppressive tumor microenvironment. SLC1A5-mediated glutamine metabolism in tumor cells modulated CD8 T cell infiltration and effector function, reshaping tumor responses to immune checkpoint blockade therapy. Glucose deprivation up-regulated SLC1A5 isoforms in tumor cells, enhancing glutamine uptake and glutathione synthesis. This adaptation limited mitochondrial oxidative stress and cytosolic mitochondrial DNA release, thereby suppressing cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) activation, interferon-β production, and CD8 T cell antitumor responses. These findings define a glutamine-fueled metabolic program as a barrier to tumor immunogenicity, positioning SLC1A5 as a tumor-intrinsic metabolic regulator with potential therapeutic relevance.
Authors
- Peixiang Lan (ORCID: https://orcid.org/0000-0001-7569-894X)
- Zhao Huang (ORCID: https://orcid.org/0000-0002-1151-4942)
- Wanguang Zhang (ORCID: https://orcid.org/0000-0003-3184-9907)
- Wei Yan (ORCID: https://orcid.org/0000-0003-3978-7675)
- Lin Xue (ORCID: https://orcid.org/0000-0001-8746-1974)
- Shenqi Han (ORCID: https://orcid.org/0009-0009-4186-7368)
- X Y Feng (ORCID: https://orcid.org/0000-0001-8826-6310)
- Xiaoping Chen (ORCID: https://orcid.org/0000-0001-8636-0493)
- Wenjun Jia (ORCID: https://orcid.org/0000-0003-0170-6729)
- Xinling Zhang (ORCID: https://orcid.org/0000-0003-3783-0465)
- Jia Liang (ORCID: https://orcid.org/0000-0003-4855-6756)
- Zhibo Ma (ORCID: https://orcid.org/0009-0006-0747-5916)
- Huifang Liang (ORCID: https://orcid.org/0000-0001-6874-3634)
- Chenglong Zeng
- Guanxing Yu
- Ran Tao
- Ganxun Li
- Bixiang Zhang (ORCID: https://orcid.org/0000-0001-5951-424X)
- Wei Yan (ORCID: https://orcid.org/0009-0005-4528-6203)
Institutions
- Jinyintan Hospital (CN)
- Wuhan University (CN)
- Third Affiliated Hospital of Zhengzhou University (CN)
- Tongji Hospital (CN)
- Huazhong University of Science and Technology (CN)
Publication Details
- Journal
- Science Immunology
- Published
- 2026-09-18
- DOI
- https://doi.org/10.1126/sciimmunol.aea4179
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Huazhong University of Science and Technology