Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy

Immune-responsive gene 1 (IRG1) encodes aconitate decarboxylase (ACOD1) that catalyzes the production of itaconic acids (ITAs). The anti-inflammatory function of IRG1/ITA has been established in multiple pathogen models, but very little is known in cancer. Here, we show that IRG1 is expressed in tumor-associated macrophages (TAMs) in both human and mouse tumors. Mechanistically, tumor cells induce Irg1 expression in macrophages by activating NF-κB pathway, and ITA produced by ACOD1 inhibits TET DNA dioxygenases to dampen the expression of inflammatory genes and the infiltration of CD8+ T cells into tumor sites. Deletion of Irg1 in mice suppresses the growth of multiple tumor types and enhances the efficacy of anti–PD-(L)1 immunotherapy. Our study provides a proof of concept that ACOD1 is a potential target for immune-oncology drugs and IRG1-deficient macrophages represent a potent cell therapy strategy for cancer treatment even in pancreatic tumors that are resistant to T cell–based immunotherapy.

• Publication year

  2023

• Venue

  Science Advances

• Publication date

  2023-04-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1126/sciadv.adg0654PMID 37115931PMCID 10146892
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Myeloid cell-targeted therapies for solid tumours

  2022cited by this paper
• Macrophage diversity in cancer revisited in the era of single-cell omics.

  2022cited by this paper
• Itaconate is a lysosomal inducer that promotes antibacterial innate immunity.

  2022cited by this paper
• Discovery and Application of Postnatal Nucleus Pulposus Progenitors Essential for Intervertebral Disc Homeostasis and Degeneration

  2022cited by this paper
• Myeloid-derived itaconate suppresses cytotoxic CD8+ T cells and promotes tumour growth.

  2022cited by this paper
• The expanding role for small molecules in immuno-oncology

  2022cited by this paper
• Promises and challenges of adoptive T-cell therapies for solid tumours

  2021cited by this paper
• Key chemokines direct migration of immune cells in solid tumors

  2021cited by this paper
• A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells.

  2021cited by this paper
• Analysis of classical neutrophils and polymorphonuclear myeloid-derived suppressor cells in cancer patients and tumor-bearing mice

  2021cited by this paper
• Single-cell RNA-Seq analysis of diabetic wound macrophages in STZ-induced mice

  2021cited by this paper
• The allergy mediator histamine confers resistanceto immunotherapy in cancer patients via activationof the macrophage histamine receptor H1.

  2021cited by this paper
• Itaconate inhibits TET DNA dioxygenases to dampen inflammatory responses

  2021cited by this paper
• Macrophages Derived From Human Induced Pluripotent Stem Cells: The Diversity of Protocols, Future Prospects, and Outstanding Questions

  2021cited by this paper
• Intratumoral SIRPα-deficient macrophages activate tumor antigen-specific cytotoxic T cells under radiotherapy

  2021cited by this paper
• Human chimeric antigen receptor macrophages for cancer immunotherapy

  2020cited by this paper
• Pan-cancer analysis of whole genomes

  2020cited by this paper
• Single-cell analysis reveals new evolutionary complexity in uveal melanoma

  2020cited by this paper
• Immune‐Responsive Gene 1/Itaconate Activates Nuclear Factor Erythroid 2–Related Factor 2 in Hepatocytes to Protect Against Liver Ischemia–Reperfusion Injury

  2020cited by this paper
• EPIC: A Tool to Estimate the Proportions of Different Cell Types from Bulk Gene Expression Data.

  2020cited by this paper
• Single-Cell Analyses Inform Mechanisms of Myeloid-Targeted Therapies in Colon Cancer.

  2020cited by this paper
• In vivo anticancer activity of a rhodium metalloinsertor in the HCT116 xenograft tumor model

  2020cited by this paper
• Targeting tumor-associated macrophages and granulocytic-myeloid-derived suppressor cells augments pd-1 blockade in cholangiocarcinoma.

  2020cited by this paper
• Itaconate controls the severity of pulmonary fibrosis

  2020cited by this paper
• Tumor suppressor TET2 promotes cancer immunity and immunotherapy efficacy.

  2019cited by this paper
• S-glycosylation-based cysteine profiling reveals regulation of glycolysis by itaconate

  2019cited by this paper
• Phagocytosis by macrophages depends on histamine H2 receptor signaling and scavenger receptor 1

  2019cited by this paper
• In vivo epigenetic CRISPR screen identifies Asf1a as an immunotherapeutic target in Kras-mutant lung adenocarcinoma.

  2019cited by this paper
• The Nucleotide Sensor ZBP1 and Kinase RIPK3 Induce the Enzyme IRG1 to Promote an Antiviral Metabolic State in Neurons

  2019cited by this paper
• The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy

  2019cited by this paper
• Attenuated inflammatory response of monocyte-derived macrophage from patients with BD: a preliminary report

  2019cited by this paper
• Neutrophils Driving Unconventional T Cells Mediate Resistance against Murine Sarcomas and Selected Human Tumors

  2019cited by this paper
• Electrophilic properties of itaconate and derivatives regulate the IκBζ–ATF3 inflammatory axis

  2018cited by this paper
• SNIP1 Recruits TET2 to Regulate c-MYC Target Genes and Cellular DNA Damage Response

  2018cited by this paper
• Targeting macrophages: therapeutic approaches in cancer

  2018cited by this paper
• Irg1 expression in myeloid cells prevents immunopathology during M. tuberculosis infection

  2018cited by this paper
• Blocking fatty acid–fueled mROS production within macrophages alleviates acute gouty inflammation

  2018cited by this paper
• Chimeric Antigen Receptor Therapy.

  2018cited by this paper
• Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors

  2018cited by this paper
• Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1

  2018cited by this paper
• CD155T/TIGIT Signaling Regulates CD8+ T-cell Metabolism and Promotes Tumor Progression in Human Gastric Cancer.

  2017cited by this paper
• Tissue‐Resident Macrophages in Pancreatic Ductal Adenocarcinoma Originate from Embryonic Hematopoiesis and Promote Tumor Progression

  2017cited by this paper
• Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels*

  2016cited by this paper
• Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation.

  2016cited by this paper
• The catalytic activity of TET2 is essential for its myeloid malignancy-suppressive function in hematopoietic stem/progenitor cells

  2016cited by this paper
• STAT3 in CD8+ T Cells Inhibits Their Tumor Accumulation by Downregulating CXCR3/CXCL10 Axis

  2015cited by this paper
• The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans

  2015cited by this paper
• Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production

  2013cited by this paper
• Immunoresponsive gene 1 augments bactericidal activity of macrophage-lineage cells by regulating β-oxidation-dependent mitochondrial ROS production.

  2013cited by this paper
• Distinct Roles for the NF-κB RelA Subunit during Antiviral Innate Immune Responses

  2011cited by this paper
• Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm

  2010cited by this paper
• Cloning and analysis of gene regulation of a novel LPS-inducible cDNA

  1995cited by this paper

• Cascade-mediated hepato-escape and targeted co-delivery of LNPs reverse TAM-mediated immunosuppression for immunotherapy and metastasis suppression in cancer

  2026cites this paper
• Obstacles and improvement strategies for CAR-T cell therapy in solid tumors

  2026cites this paper
• Itaconate and its derivatives ameliorate autoimmunity by suppressing Th17 cells via regulating mitophagy

  2026cites this paper
• From innate-like to innate: the next wave of off-the-shelf CAR immunotherapies

  2026cites this paper
• Emerging Role of ACOD1/Itaconate in Cancer: Bridging Metabolic Reprogramming and Signaling in the Tumor Microenvironment

  2026cites this paper
• Macrophages: Targets for next-generation cancer immunotherapy.

  2026cites this paper
• ACOD1 expression in patients with sepsis: an exploratory study of associations with disease severity and immune signatures.

  2026cites this paper
• Immunometabolites and cancer: the role of 2-hydroxyglutarate, succinate, fumarate and itaconate in tumour development and anti-tumour immunity.

  2026cites this paper
• Targeting Acod1/itaconate in Cancer Therapy: Mechanisms and Opportunities.

  2026cites this paper
• Therapeutic targeting of toll-like receptor pathways in tumor-associated macrophages.

  2026cites this paper
• Molecular Targets for Cancer Immunotherapy: Focusing on (Immune and Tumor) Cell-Derived Metabolites

  2026cites this paper
• Stromal cell-derived itaconate promotes endometriosis via macrophage NRF2 and lysosomal pH modulation.

  2026cites this paper
• Extracellular vesicles as natural nanocarriers: From in vitro engineering to in situ generation in cancer therapy

  2025cites this paper
• Itaconate targets the ERK2 signal to suppress estrogen receptor-positive breast cancer cell growth.

  2025cites this paper
• Gang of 3: How the Krebs cycle-linked metabolites itaconate, succinate, and fumarate regulate macrophages and inflammation.

  2025cites this paper
• Unveiling the crossroads of STING signaling pathway and metabolic reprogramming: the multifaceted role of the STING in the TME and new prospects in cancer therapies

  2025cites this paper
• Engineering innate immune cells for cancer immunotherapy

  2025cites this paper
• CAR T cell-driven induction of iNOS in tumor-associated macrophages promotes CAR T cell resistance in B cell lymphoma

  2025cites this paper
• Myeloid-lineage-specific membrane protein LRRC25 suppresses immunity in solid tumor and is a potential cancer immunotherapy checkpoint target.

  2025cites this paper
• Itaconate: A Potential Therapeutic Strategy for Autoimmune Disease

  2025influential citation
• 4-Octyl Itaconate Modulates Dendritic Cells Function and Tumor Immunity via NRF2 Activation

  2025cites this paper
• Hydrogen activates ACOD1-itaconate pathway to ameliorate steroid-associated osteonecrosis.

  2025cites this paper
• Radiation-induced upregulation of itaconate in macrophages promotes the radioresistance of non-small cell lung cancer by stabilizing NRF2 protein and suppressing immune response

  2025cites this paper
• Targeting myeloid cell immunometabolism to improve current non-small cell lung cancer therapies.

  2025cites this paper
• Inflammatory macrophage-derived itaconate inhibits DNA demethylase TET2 to prevent excessive osteoclast activation in rheumatoid arthritis

  2025cites this paper
• Boosting mRNA cancer vaccine efficacy via targeting Irg1 on macrophages in lymph nodes

  2025cites this paper
• Glycolytic reprogramming in macrophage polarization: New horizons in the treatment of tumor diseases.

  2025cites this paper
• Irg1-Mediated Inhibition of A20 Triggers NF-κB Signaling Cascade in Tilapia Macrophages during Early Immune Response.

  2025cites this paper
• Spectroscopic method for measuring activity of cis-Aconitate Decarboxylase, an important metabolic regulator of immune responses.

  2025cites this paper
• Small intestinal γδ T17 cells promote SAE through STING/C1q-induced microglial synaptic pruning in male mice

  2025cites this paper
• Reprogramming tumor-associated macrophages and blocking PD-L1 via engineered outer membrane vesicles to enhance T cell infiltration and cytotoxic functions

  2025cites this paper
• Itaconate: A key regulator of immune responses and potential therapeutic target for autoimmune and inflammatory diseases.

  2025cites this paper
• Targeting SPHK1 in macrophages remodels the tumor microenvironment and enhances anti‐PD‐1 immunotherapy efficacy in colorectal cancer liver metastasis

  2025cites this paper
• Macrophage Reprogramming: Emerging Molecular Therapeutic Strategies for Nephrolithiasis

  2025cites this paper
• Glucose metabolism and its direct action in cancer and immune regulation: opportunities and challenges for metabolic targeting

  2025cites this paper
• Targeted photodynamic therapy: enhancing efficacy through specific organelle engagement

  2025cites this paper
• Targeting macrophages in cancer immunotherapy: Frontiers and challenges

  2025cites this paper
• TCA cycle-derived oncometabolites in cancer and the immune microenvironment

  2025cites this paper
• In vivo itaconate tracing reveals degradation pathway and turnover kinetics

  2025cites this paper
• Post-translational governance of NF-κB in cancer immunity: mechanisms and therapeutic horizons

  2025cites this paper
• IRG1/itaconate/NRF2/GSH axis in tumor-associated macrophages drives therapy resistance and immune evasion in BRCA1-deficient breast cancer

  2025cites this paper
• Itaconate is metabolized to 2-hydroxymethylsuccinate through a CoA-independent degradation pathway in mitochondria

  2025cites this paper
• Fatty Acid Oxidation Metabolites in Aquatic Animals: Metabolic Pathway, Dynamic Remodeling, and Functional Implications

  2025cites this paper
• Demystifying metabolic‒immune crosstalk: how amino acid metabolic reprogramming shapes the malignant phenotype and macrophage polarization of biliary and pancreatic tumors

  2025cites this paper
• Intraperitoneal metastasis of gastric cancer: new insights on resident macrophages.

  2025cites this paper
• Akt inhibition enhances the antitumor efficacy of immune checkpoint blockades and radiotherapy in a syngeneic breast cancer model

  2025cites this paper
• Targeting Metabolic Reprogramming in Tumor: From Mechanisms to Precision Immunotherapies

  2025cites this paper
• Fucosyltransferase 8‐Derived Circular RNA Drives M2 Polarization of Macrophages Through ENO1‐TNF Signaling Axis to Promote Lung Cancer Progression

  2025cites this paper
• Vascular Smooth Muscle Cell-Specific BCAT2 Deficiency Attenuates Diabetic Atherosclerotic Calcification via Histone Propionylation

  2025cites this paper
• miR-34a-5p Accelerates Osteoporotic Fracture Healing by Suppressing Foxp1 and Modulating Hippo/YAP-Mediated Bone Remodeling

  2025cites this paper
• Regulatory T Cell Metabolism in Cancer

  2025cites this paper
• Immune Regulation of Itaconate and Its Derivatives in Liver Diseases

  2025influential citation
• Itaconate transporter SLC13A3 confers immunotherapy resistance via alkylation-mediated stabilization of PD-L1.

  2025cites this paper
• Complement C3 of tumor-derived extracellular vesicles promotes metastasis of RCC via recruitment of immunosuppressive myeloid cells

  2025cites this paper
• Linking macrophage metabolism to function in the tumor microenvironment

  2025cites this paper
• Targeting IRG1 in tumor-associated macrophages for cancer therapy

  2025cites this paper
• MMP28 recruits M2-type tumor-associated macrophages through MAPK/JNK signaling pathway-dependent cytokine secretion to promote the malignant progression of pancreatic cancer

  2025cites this paper
• GDP-bound Rab37 modulates M2-like tumor-associated macrophage polarization by attenuating STAT1 translocation to downregulate the type I IFN pathway

  2025cites this paper
• Targeted Delivery of α‐ketoglutarate to Macrophages in Bone: A Novel Therapeutic Strategy for Improving Fracture Healing in Type 2 Diabetes

  2025cites this paper
• From silent partners to potential therapeutic targets: macrophages in colorectal cancer

  2025cites this paper
• Immunometabolism of tumor-associated macrophages: A therapeutic perspective.

  2025cites this paper
• Myeloid cells: key players in tumor microenvironments

  2025cites this paper
• Itaconate restrains acute proinflammatory activation of microglia MG after traumatic brain injury in mice.

  2025cites this paper
• Myeloid cells meet CD8+ T cell exhaustion in cancer: What, why and how.

  2024cites this paper
• ABCG2 is an itaconate exporter that limits antibacterial innate immunity by alleviating TFEB-dependent lysosomal biogenesis.

  2024cites this paper
• Metabolic regulation of tumor-associated macrophage heterogeneity: insights into the tumor microenvironment and immunotherapeutic opportunities

  2024cites this paper
• IRG1 restrains M2 macrophage polarization and suppresses intrahepatic cholangiocarcinoma progression via the CCL18/STAT3 pathway

  2024cites this paper
• Deciphering metabolic crosstalk in context: lessons from inflammatory diseases

  2024cites this paper
• Progress of Itaconate in the Treatment of Renal Diseases

  2024cites this paper
• Itaconate impairs immune control of Plasmodium by enhancing mtDNA-mediated PD-L1 expression in monocyte-derived dendritic cells.

  2024cites this paper
• Fatty acid metabolism-related lncRNA prognostic signature for serous ovarian carcinoma.

  2024cites this paper
• Control of immune cell signaling by the immuno-metabolite itaconate

  2024cites this paper
• CSF1R inhibition reprograms tumor-associated macrophages to potentiate anti-PD-1 therapy efficacy against colorectal cancer.

  2024cites this paper
• Itaconate in host inflammation and defense.

  2024cites this paper
• Leveraging macrophage metabolism for anticancer therapy: opportunities and pitfalls.

  2024cites this paper
• Embracing cancer complexity: Hallmarks of systemic disease.

  2024cites this paper
• An Epic Advancement in Targeting Macrophages for Cancer Therapy Approach.

  2024cites this paper
• Itaconate as a key player in cardiovascular immunometabolism.

  2024cites this paper
• FAM53B promotes pancreatic ductal adenocarcinoma metastasis by regulating macrophage M2 polarization

  2024cites this paper
• Activating innate immune responses repolarizes hPSC-derived CAR macrophages to improve anti-tumor activity.

  2024cites this paper
• A quick and innovative pipeline for producing chondrocyte-homing peptide-modified extracellular vesicles by three-dimensional dynamic culture of hADSCs spheroids to modulate the fate of remaining ear chondrocytes in the M1 macrophage-infiltrated microenvironment

  2024cites this paper
• Tumor-Associated Senescent Macrophages, Their Markers, and Their Role in Tumor Microenvironment

  2024cites this paper
• A new era of cancer immunotherapy: combining revolutionary technologies for enhanced CAR-M therapy

  2024cites this paper
• Enhancing cancer immunotherapy: Nanotechnology-mediated immunotherapy overcoming immunosuppression

  2024cites this paper
• The Oncolytic virus VT1092M and an Anti-PD-L1 antibody synergize to induce systemic antitumor immunity in a murine bilateral tumor model

  2024cites this paper
• Biointerface‐Engineered Hybrid Nanovesicles for Targeted Reprogramming of Tumor Microenvironment

  2024cites this paper
• Protocol for building an in vitro model of M2-like tumor-associated macrophages with lactic acid or conditioned medium from Lewis cells

  2024cites this paper
• Oncometabolites in cancer: from cancer cells to the tumor microenvironment

  2024cites this paper
• Aconitate decarboxylase (ACOD1) has found a disease.

  2024cites this paper
• The potential therapeutic role of itaconate and mesaconate on the detrimental effects of LPS-induced neuroinflammation in the brain

  2024cites this paper
• Itaconate uptake via SLC13A3 improves hepatic antibacterial innate immunity.

  2024cites this paper
• Tumor-associated macrophage-derived itaconic acid contributes to nasopharyngeal carcinoma progression by promoting immune escape via TET2

  2024cites this paper
• Tumor-associated macrophages within the immunological milieu: An emerging focal point for therapeutic intervention

  2024cites this paper
• Drug resistance and tumor immune microenvironment: An overview of current understandings (Review)

  2024cites this paper
• Toward decoding spatiotemporal signaling activities of reactive immunometabolites with precision immuno-chemical biology tools

  2024cites this paper
• Hematopoietic aging promotes cancer by fueling IL-1α-driven emergency myelopoiesis

  2024cites this paper
• Metabolic reprogramming of macrophages in cancer therapy.

  2024cites this paper
• Cancer cell-intrinsic biosynthesis of itaconate promotes tumor immunogenicity

  2024influential citation
• Pharmacological upregulation of macrophage-derived itaconic acid by pubescenoside C attenuated myocardial ischemia–reperfusion injury

  2024cites this paper
• The role and therapeutic potential of itaconate in lung disease

  2024cites this paper