ArticleScience advances2023
Inhibition of ACLY overcomes cancer immunotherapy resistance via polyunsaturated fatty acids peroxidation and cGAS-STING activation.
Article in Science advances, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers.
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Who cites it
89 citing papers in PubMed, 125 citations in OpenAlex.
- Metabolic reprogramming in colorectal cancer: Mechanisms and therapeutic insights.Genes & diseases · 2027Review
- Nanoadjuvant-based membrane poration boosts antitumor immunity via modulating mitochondrial metabolism to downregulate PD-L1 and upregulate STING.Bioactive materials · 2027Article
- Bone Marrow Macrophage STING Signaling is a Direct Nexus Linking Marrow Adipose Expansion to NADAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Metabolic immune checkpoints (MICs) in cancer: from molecular mechanisms to challenges and opportunities in clinical translation.Signal transduction and targeted therapy · 2026Review
- The cGAS-STING pathway: mechanistic basis, dual biological functions and translational therapeutic advances.Apoptosis : an international journal on programmed cell death · 2026Review
- The cGAS-STING Pathway: A Double-Edged Regulator of Neuroinflammation and Myelin Regeneration.Molecular neurobiology · 2026Review
- The Cancer Cell Metabolic Reprogramming Remodels the Tumor Microenvironment: Molecular Mechanisms and Therapeutic Strategies.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- cGAS-STING Modulates the NF-κB Pathway to Influence the Occurrence of Ulcerative Colitis-Associated Colorectal Cancer.Digestive diseases and sciences · 2026Article
- PGK1-driven histone lactylation fuels MDSC-driven immune evasion and tumor progression in triple-negative breast cancer.Acta pharmacologica Sinica · 2026Article
- SIRT1 Inhibits T-cell Infiltration and Tertiary Lymphoid Structure Formation to Promote Radioimmunotherapy Resistance.Cancer research · 2026Article
- Glucose restriction reprograms lipid metabolism and enhances immunotherapy through ZNRF3-Wnt-SCD signaling axis.Journal for immunotherapy of cancer · 2026Article
- Article
- P4HA3 drives cervical cancer lymphatic metastasis by facilitating ACLY-mediated ferroptosis resistance.Cell death and differentiation · 2026Article
- EEPD1 Inhibition Unleashes Antitumor Immunity in Colorectal Cancer by Activating the cGAS-STING Pathway.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- The role of tumor metabolic reprogramming in acquired anti-PD-1/PD-L1 resistance.Translational lung cancer research · 2026Review
- De Novo Lipogenesis in Clear Cell Renal Cell Carcinoma: Mechanistic Insights and Therapeutic Implications.International journal of molecular sciences · 2026Review
- Repositioning ACLY in liver cancer: from metabolic enzyme to a regulator of antitumor immunity.Science China. Life sciences · 2026Article
- Research progress and therapeutic strategies in hepatocellular carcinoma metabolic reprogramming.Journal of advanced research · 2026Review
- Lipid metabolism reprogramming shapes the immune landscape in the tumor microenvironment.Cellular & molecular immunology · 2026Review
- The GOLM1-ACLY pathway regulates macrophage-secreted EFEMP1 via H3K27ac modifications to drive tumor progression.Journal of advanced research · 2026Article
29 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Adenosine 5'-triphosphate citrate lyase (ACLY) is a cytosolic enzyme that converts citrate into acetyl-coenzyme A for fatty acid and cholesterol biosynthesis. ACLY is up-regulated or activated in many cancers, and targeting ACLY by inhibitors holds promise as potential cancer therapy. However, the role of ACLY in cancer immunity regulation remains poorly understood. Here, we show that ACLY inhibition up-regulates PD-L1 immune checkpoint expression in cancer cells and induces T cell dysfunction to drive immunosuppression and compromise its antitumor effect in immunocompetent mice. Mechanistically, ACLY inhibition causes polyunsaturated fatty acid (PUFA) peroxidation and mitochondrial damage, which triggers mitochondrial DNA leakage to activate the cGAS-STING innate immune pathway. Pharmacological and genetic inhibition of ACLY overcomes cancer resistance to anti-PD-L1 therapy in a cGAS-dependent manner. Furthermore, dietary PUFA supplementation mirrors the enhanced efficacy of PD-L1 blockade by ACLY inhibition. These findings reveal an immunomodulatory role of ACLY and provide combinatorial strategies to overcome immunotherapy resistance in tumors.
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