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Synthesis and Characterization of an Aspirin-fumarate Prodrug that Inhibits NFκB Activity and Breast Cancer Stem Cells
Published on: January 18, 2017
ADSL-generated fumarate binds and inhibits STING to promote tumour immune evasion
Yuran Duan1,2,3, Zhiqiang Hu1,2,3, Peng Han4
1Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
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.
Insights
Breast cancer cells evade immune detection by hijacking the cGAS-STING pathway. Hypoxia-activated ADSL enzyme produces fumarate, inhibiting STING and promoting tumor growth, offering new therapeutic targets.
Area of Science:
- Immunology and Cancer Biology
- Metabolic pathways in cancer
Background:
- Highly aggressive tumors evade immune surveillance by suppressing the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway.
- Mechanisms by which cancer cells hijack the cGAS-STING pathway for immune evasion are largely unknown.
Purpose of the Study:
- To elucidate the mechanisms by which breast cancer cells restrain cGAS-STING pathway activation.
- To identify novel therapeutic strategies targeting cancer immune evasion.
Main Methods:
- Investigated STING activation under hypoxia in normal mammary epithelial cells versus breast cancer cells.
- Examined the role of adenylosuccinate lyase (ADSL) expression, phosphorylation at T350 by IKKβ, and its interaction with STING.
- Assessed the impact of fumarate production by ADSL on STING activation and downstream signaling.
- Evaluated therapeutic interventions including ADSL translocation inhibition and anti-PD-1 antibody treatment.
Main Results:
- Hypoxia robustly activates STING in normal cells but not in breast cancer cells.
- Hypoxia-activated IKKβ phosphorylates ADSL at T350 in breast cancer cells; phosphorylated ADSL interacts with STING.
- ADSL-produced fumarate binds STING, inhibiting cGAMP binding, STING activation, and IRF3-dependent cytokine expression.
- Disrupting ADSL-STING interaction enhances STING activation and suppresses tumor growth.
- Combination therapy with ADSL inhibitor and anti-PD-1 antibody shows additive tumor growth inhibition and increased immune response.
- High ADSL T350 phosphorylation correlates inversely with STING activation and predicts poor prognosis in breast cancer patients.
Conclusions:
- ADSL plays a critical role in mediating STING inhibition in breast cancer via fumarate production.
- Targeting the ADSL-STING interaction presents a promising strategy to enhance anti-tumor immunity and improve immunotherapy efficacy.
- ADSL T350 phosphorylation serves as a potential prognostic biomarker for breast cancer.
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