ArticleNature immunology2022
PERK is a critical metabolic hub for immunosuppressive function in macrophages.
Article in Nature immunology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 157 papers.
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Who cites it
157 citing papers in PubMed, 207 citations in OpenAlex.
- Necroptosis-related diseases are regulated by the unfolded protein response during endoplasmic reticulum stress.Genes & diseases · 2027Review
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- Targeting myeloid cell plasticity and metabolic reprogramming to alleviate T cell dysfunction and exhaustion-associated states and enhance immune checkpoint blockade therapy.Biomarker research · 2026Review
- The Unfolded Protein Response as a Modulator of Cancer-Immune Cell Communication in the Tumour Microenvironment.Journal of cellular and molecular medicine · 2026Review
- Article
- Inhibition of PERK signaling suppresses tumor progression and blocks GP73-GRP78-dependent stromal activation in hepatocellular carcinoma.Neoplasia (New York, N.Y.) · 2026Article
- Muscularis EGR1 Deficiency Impairs M2 Macrophage Polarization and Disrupts Gastric Motility in Diabetic Gastroparesis.Neurogastroenterology and motility · 2026Article
- Unconventional role of hydroxymethylglutaryl-CoA synthase 1 in driving pathogenic TScience advances · 2026Article
- β-glucan elicits APOE-dependent peripheral trained immunity to suppress hepatocellular carcinoma.Journal for immunotherapy of cancer · 2026Article
- Treatment with saponins fromNutrition research and practice · 2026Article
- UPR-CEBPB-MIF Signaling Links to Macrophage Polarization and an Immunosuppressive Tumor Microenvironment in Clear Cell Renal Cell Carcinoma.Annals of surgical oncology · 2026Article
- Endoplasmic Reticulum Stress-Induced Endothelial Cell Pyroptosis Contributes to Pulmonary Vascular Remodeling and Pulmonary Arterial Hypertension via IRE1α/Caspase-3/GSDME Pathway.Journal of the American Heart Association · 2026Article
- CCR7-PERK-CREB3L1 signaling mediates tumor-associated macrophages-derived SPP1 promotion of oral squamous cell carcinoma.Communications biology · 2026Article
- Distinct macrophage and T cell programs shape pancreatic inflammation during metabolic stress and aging.bioRxiv : the preprint server for biology · 2026Article
- Multifunctional Role of Mitochondrial Fatty Acid Oxidation in Cancer Immunotherapy and Aging.Cancer science · 2026Review
- Cold Atmospheric Plasma-Activated Decellularized Extracellular Matrix Gel as a Tumor-Infiltrating Immunoactivation Platform for Post-Surgical Cancer Immunotherapy.Advanced materials (Deerfield Beach, Fla.) · 2026Article
- Multifunctional nanotherapeutics for targeted modulation of endoplasmic reticulum stress to potentiate cancer therapy.Asian journal of pharmaceutical sciences · 2026Review
- Dynamic remodeling of amino acid metabolism in tumor-associated macrophages: Fueling immunosuppression, reshaping tumor niches, and unlocking metabolic checkpoints.Journal of advanced research · 2026Review
- ATF4 promotes immune evasion in oral squamous cell carcinoma by suppressing autophagic PD-L1 degradation.Journal for immunotherapy of cancer · 2026Article
- Endoplasmic reticulum stress in antitumor immunity and immunotherapy resistance: mechanisms and therapeutic implications.Molecular cancer · 2026Review
97 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors at 7 institutions in 4 countries.
Funding
Abstract
Chronic inflammation triggers compensatory immunosuppression to stop inflammation and minimize tissue damage. Studies have demonstrated that endoplasmic reticulum (ER) stress augments the suppressive phenotypes of immune cells; however, the molecular mechanisms underpinning this process and how it links to the metabolic reprogramming of immunosuppressive macrophages remain elusive. In the present study, we report that the helper T cell 2 cytokine interleukin-4 and the tumor microenvironment increase the activity of a protein kinase RNA-like ER kinase (PERK)-signaling cascade in macrophages and promote immunosuppressive M2 activation and proliferation. Loss of PERK signaling impeded mitochondrial respiration and lipid oxidation critical for M2 macrophages. PERK activation mediated the upregulation of phosphoserine aminotransferase 1 (PSAT1) and serine biosynthesis via the downstream transcription factor ATF-4. Increased serine biosynthesis resulted in enhanced mitochondrial function and α-ketoglutarate production required for JMJD3-dependent epigenetic modification. Inhibition of PERK suppressed macrophage immunosuppressive activity and could enhance the efficacy of immune checkpoint programmed cell death protein 1 inhibition in melanoma. Our findings delineate a previously undescribed connection between PERK signaling and PSAT1-mediated serine metabolism critical for promoting immunosuppressive function in M2 macrophages.
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