Dynamic regulation of lysine and arginine metabolism promotes immune evasion by limiting T cell function in cancer
Tumor cells promote metabolic dysregulation of immune cells by controlling the metabolic landscape of the tumor microenvironment. It is unclear whether tumors restrict specific nutrients to drive rapid growth and immune evasion in addition to the overconsumption of nutrients to support anabolism. We identified that up-regulation of solute carrier family 7 member 1 (SLC7A1) increased arginine utilization and promoted tumor growth, whereas down-regulation of SLC7A2 decreased lysine catabolism to support immune evasion. Repression of lysine catabolism in tumor cells reduced glutaconic acid (GC), a medium-chain acyl-CoA dehydrogenase–dependent lysine catabolite that has immunostimulatory effects on antitumor CD8 T cells. GC modified pyruvate kinase M2 (PKM2) through posttranslational glutaconylation at key lysine residues Lys 336 (K336) and K337. This modification reinforced PKM2 dimers, transcriptionally driving metabolic reprogramming and reinvigorating antitumor CD8 T cells. Our study highlights an amino acid trade-off that dynamically optimizes the metabolic preferences of tumors to promote proliferation and immune evasion.
Authors
- Lihao Chen
- Qianzhou Yu (ORCID: https://orcid.org/0000-0001-9979-6210)
- Dehang Yang
- Ruya Sun (ORCID: https://orcid.org/0009-0005-4696-7801)
- Fan Yang (ORCID: https://orcid.org/0000-0002-0520-5254)
- Qian Xiao (ORCID: https://orcid.org/0000-0002-0120-2371)
- Tianyi Hu (ORCID: https://orcid.org/0000-0003-0013-0991)
- Siwen Zhang (ORCID: https://orcid.org/0000-0002-7314-641X)
- Sheng Chen (ORCID: https://orcid.org/0000-0002-5186-5069)
- Siqi Dai (ORCID: https://orcid.org/0000-0002-5729-6768)
- Xiaoyang Lu
- Kefeng Ding (ORCID: https://orcid.org/0000-0002-2380-3717)
- Weiwei Yu (ORCID: https://orcid.org/0000-0001-5230-8515)
- Yidong Yang (ORCID: https://orcid.org/0000-0002-3892-1687)
- Zhexu Chi
- Di Wang (ORCID: https://orcid.org/0000-0002-2712-1705)
- Zhen Wang (ORCID: https://orcid.org/0000-0003-4134-1779)
- Heng Zhang (ORCID: https://orcid.org/0000-0003-0620-7638)
- Yiyi Zhu (ORCID: https://orcid.org/0000-0003-1184-8333)
- Quanquan Wang (ORCID: https://orcid.org/0000-0001-8092-4040)
- Jian Zhang (ORCID: https://orcid.org/0000-0003-2807-2463)
- Xiangyuan Li
- Qiqi Deng (ORCID: https://orcid.org/0009-0003-2235-6139)
Institutions
- Zhejiang Chinese Medical University (CN)
- Sir Run Run Shaw Hospital (CN)
- Zhejiang Cancer Hospital (CN)
- Ministry of Education (IR)
- Centre d'études et de recherches internationales de Sciences Po (FR)
- Second Affiliated Hospital of Zhejiang University (CN)
- First Affiliated Hospital Zhejiang University (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- Science Immunology
- Published
- 2026-07-24
- DOI
- https://doi.org/10.1126/sciimmunol.aeb7315
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Ministry of Education of the People's Republic of China
- School of Medicine, Shahid Beheshti University of Medical Sciences
- National Key Research and Development Program of China
- Key Research and Development Program of Zhejiang Province