Evidence map›Paper›PMID 42222880›Full record

ArticleThe Journal of clinical investigation2026

Aspartate deficiency amplifies cGAS-STING signaling in antitumor immunity.

Yuheng Liao, Hanze Wang, Hengxin Liu, Xi Chen, Renqiang Sun, Xie Li, Zhen Yang, Chenying Liu, Wei Wu, Ziqian He and 4 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of clinical investigation, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Article
  2. Article
  3. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors.

Yuheng LiaoDepartment of Neurosurgery, Huashan Hospital; and Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Hanze WangInstitute for Translational Brain Research, Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
Hengxin LiuInstitute for Translational Brain Research, Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
Xi ChenInstitute for Translational Brain Research, Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
Renqiang SunDepartment of Neurosurgery, Huashan Hospital; and Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Xie LiOptogenetics & Synthetic Biology Interdisciplinary Research Center, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
Zhen YangCenter for Medical Research and Innovation of Pudong Hospital and Intelligent Medicine Institute, Shanghai Medical College, Fudan University, Shanghai, China.
Chenying LiuDepartment of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Wei WuKey Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Ziqian HeDepartment of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York, USA.
Yuzheng ZhaoOptogenetics & Synthetic Biology Interdisciplinary Research Center, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
Ying MaoDepartment of Neurosurgery, Huashan Hospital; and Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Dan YeDepartment of Neurosurgery, Huashan Hospital; and Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Hui YangDepartment of Neurosurgery, Huashan Hospital; and Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Metabolic signals critically shape innate immune responses. Through pharmacological screening of metabolic pathways, we identified aspartate metabolism as a key regulator of cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling. Genetically or aminooxyacetic acid-mediated (AOA-mediated) pharmacologically reducing aspartate levels markedly potentiated the cGAS-STING pathway, leading to stronger upregulation of type I interferons and interferon-stimulated genes. Mechanistically, disruption of de novo pyrimidine synthesis, a major downstream pathway of aspartate, induced mtDNA replication stress and increased mtDNA double-strand breaks, promoting mtDNA release into the cytosol. Cytosolic mtDNA synergized with cGAS-STING agonists to upregulate Z-DNA binding protein 1 (ZBP1), which recruits RIPK1/3 to sustain IRF3 phosphorylation, forming a positive feedback loop that amplifies innate immune signaling. In immunocompetent mouse models, AOA enhanced the antitumor efficacy of STING agonists, chemotherapy, or radiotherapy, whereas aspartate supplementation abrogated these effects. Consistently, aspartate levels negatively correlated with antitumor immunity in colorectal cancer patient samples. Together, our study identifies aspartate-pyrimidine metabolism as a critical metabolic checkpoint that licenses STING signaling by enabling mtDNA stress to cooperate with agonist stimulation, driving type I interferon-dependent ZBP1 induction and feed-forward amplification of STING signaling, thus offering a promising strategy to enhance antitumor immunity.

Indexed as

Aspartic AcidColorectal NeoplasmsImmunity, InnateMembrane ProteinsNeoplasm ProteinsNucleotidyltransferasesSignal TransductionAnimalscGAS-STING Signaling PathwayCyclic Guanosine Monophosphate-Adenosine Monophosphate SynthaseDNA, MitochondrialHumansInterferon Regulatory Factor-3MiceMice, KnockoutSTING ProteinAspartic AcidcGAS protein, humancGAS protein, mouseCyclic Guanosine Monophosphate-Adenosine Monophosphate SynthaseDNA, MitochondrialInterferon Regulatory Factor-3Membrane ProteinsNeoplasm ProteinsNucleotidyltransferasesSTING1 protein, humanSting1 protein, mouseSTING ProteinCellular immune responseMetabolismOncology

Identifiers

PMID42222880
PMCPMC13221234

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.