ArticleNature cell biology2025
ADSL-generated fumarate binds and inhibits STING to promote tumour immune evasion.
Article in Nature cell biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed.
- Metabolic regulation of calcium homeostasis via SERCA succination.Science advances · 2026Article
- Genipin induces liver injury by disrupting the CPS1-regulated urea cycle and redox homeostasis.Journal of pharmaceutical analysis · 2026Article
- Post-translational modifications in metabolic reprogramming: implications for metabolic therapy and immunotherapy in cancer.Signal transduction and targeted therapy · 2026Review
- PTX3 induces the expression of PD-L1 and promotes breast cancer immune escape.Breast cancer (Tokyo, Japan) · 2026Article
- Discovery of XNW5004 as a novel EZH2 inhibitor that enhances anti-tumor immunity and synergizes with PD-1 blockade immunotherapy in lung adenocarcinoma.Journal of translational medicine · 2026Article
- Compression-induced metabolic adaptation drives confined tumor cell migration and distant metastasis via malate-dependent microtubule reinforcement.Cell research · 2026Article
- Metabolites as signalling molecules in the tumour immune microenvironment.Nature reviews. Immunology · 2026Review
- The P2X4-P2X7 purinergic axis in alcohol-related liver disease: from fibrogenesis to immunotherapy resistance.Purinergic signalling · 2026Review
- The cGAS-STING pathway in senescence and aging-related diseases: mechanisms and therapeutic opportunities.Cell communication and signaling : CCS · 2026Review
- Nanomedicine leverages cuproptosis-mediated cGAS-STING activation to enhance antitumor immunity.Journal of nanobiotechnology · 2026Review
- Multifunctional extracellular vesicles inhibiting autophagy ameliorate immunotherapy in non-small cell lung cancer.Acta pharmaceutica Sinica. B · 2026Article
- Activating the cGAS-STING pathway in hypoxic microenvironment: blocking ADSL's ER localization.Science China. Life sciences · 2026Article
- The cGAS-STING pathway and mitochondrial metabolism: from mechanistic insights to therapeutic potential in tumor.Journal of translational medicine · 2026Review
- Mitochondrial biology and immune crosstalk in breast cancer: therapeutic opportunities and challenges.Frontiers in immunology · 2026Review
- Stimulator of interferon genes (STING)-activating nanomedicines: Translating innate immune modulation into effective therapy for triple-negative breast cancer.Clinical and translational medicine · 2026Review
- Photothermal therapy triggering organelle stress and metabolic reprogramming to potentiate antitumor immunity.Frontiers in immunology · 2026Review
- Hypoxia-driven tumor immune escape: mechanisms and therapeutic opportunities.Frontiers in immunology · 2026Review
- Adenylosuccinate lyase in pancreatic ductal adenocarcinoma chemoresistance: from purine metabolism to metabolic vulnerability.Cancer drug resistance (Alhambra, Calif.) · 2026Review
- cGAS-STING and PANoptosis: Interplay, Underlying Mechanisms, and Therapeutic Targets.Drug design, development and therapy · 2026Review
- Microbiota-driven metabolic-immune crosstalk in breast cancer.Frontiers in pharmacology · 2026Review
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Authors and funding
21 authors.
Funding
Abstract
Highly aggressive tumours have evolved to restrain the cGAS-STING pathway for immune evasion, and the mechanisms underlying this hijacking remain unknown. Here we demonstrate that hypoxia induces robust STING activation in normal mammary epithelial cells but not in breast cancer cells. Mechanistically, adenylosuccinate lyase (ADSL), a key metabolic enzyme in de novo purine synthesis, is highly expressed in breast cancer tissues and is phosphorylated at T350 by hypoxia-activated IKKβ. Phosphorylated ADSL interacts with STING at the endoplasmic reticulum, where ADSL-produced fumarate binds to STING, leading to the inhibition of cGAMP binding to STING, STING activation and subsequent IRF3-dependent cytokine gene expression. Disrupting the ADSL-STING association promotes STING activation and blunts tumour growth. Notably, a combination treatment with ADSL endoplasmic reticulum translocation-blocking peptide and anti-PD-1 antibody induces an additive inhibitory effect on tumour growth accompanying a substantially increased immune response. Notably, ADSL T350 phosphorylation levels are inversely correlated with levels of STING activation and predicate poor prognosis in patients with breast cancer. These findings highlight a pivotal role of the metabolite fumarate in inhibiting STING activation and uncover new strategies to improve immune-checkpoint therapy by targeting ADSL-moonlighting function-mediated STING inhibition.
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Registered trials
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.