Omics · study · 2026
IRG1/itaconate axis modulates lung tumor microenvironment via pentose phosphate pathway [sav25]
Listed in NCBI GEO
Tumor-associated macrophages (TAMs) are an important component of the immune milieu within the lung tumor microenvironment (TME) and have both tumor-promoting and tumor-inhibiting functions.
Description
However, the exact mechanisms underlying TAM-mediated inhibition of tumor development are still unknown. Itaconate is one of the main metabolites produced by the enzyme immune responsive gene 1 (IRG1) during a pro-inflammatory response.
Single cell RNA-seq studies show that macrophages are the major immune cells for Irg1 expression in human and mouse lung tumors. Both Irg1-deficient mice and transplantation of Irg1-depleted bone marrow resulted in increased development of lung tumors in Kras and orthotopic mouse models, suggesting the anti-tumor function of Irg1-associated macrophages. On the other hand, 4-octyl-itaconate (octyl-Ita) reduces lung tumor development in lung cancer cell lines in vitro, in vivo models of lung cancer, and ex vivo using human tumor precision-cut lung slices.
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Mechanistically, IRG1/itaconate induces a metabolic shift in cancer cells and pro-tumor macrophages, specifically through inhibition of the pentose phosphate pathway (PPP). An integrative analysis of metabolomics, transcriptomics and proteomics identified glucose-6-phosphate dehydrogenase (G6PD) as the primary target for the antiproliferative effect of IRG1/itaconate. IRG1/Itaconate inhibited G6PD activity without affecting G6PD expression in Irg1-deficient mice and octyl Ita-treated lung cancer models.
The novel inhibitory effects of IRG1/Itaconate and Octyl Ita on G6PD activity and PPP metabolism can not only suppress cancer cell proliferation in a non-cell-autonomous manner, but also re-educate pro-tumor macrophages into anti-tumor macrophages in a cell-autonomous manner. Our results suggest that octyl Ita is an effective anti-tumor metabolite with potential therapeutic application in lung cancer.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE256nnn/GSE256044 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE256044 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1077934 ncbi.nlm.nih.gov/bioproject/PRJNA1077934 ↗
project · from NCBI GEO
- PubMed 42235511 pubmed.ncbi.nlm.nih.gov/42235511 ↗
publication · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Homo sapiens
- From keywords
- Life Sciences
- Inferred from text
- Cancer 75% · Mass spectrometry 65% · RNA sequencing 65%
Provenance · 1 source records, 10 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE256044 | 12 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[disease].local:disease:cancer | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[modality].local:modality:mass-spectrometry | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (65%) |
| concepts[modality].local:modality:rna-seq | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (65%) |
| concepts[organism].NCBITaxon:9606 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |