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| Status |
Public on Sep 19, 2024 |
| Title |
Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance [RNA-Seq] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Immune checkpoint blockade (ICB) triggers tumor ferroptosis. However, most patients are unresponsive to ICB. Tumors might evade ferroptosis in the tumor microenvironment (TME). Here, we discovered SLC13A3 is an itaconate transporter in tumor cells and endows tumor ferroptosis resistance, diminishing tumor immunity and ICB efficacy. Mechanistically, tumor cells uptake itaconate via SLC13A3 from tumor-associated macrophages (TAMs), thereby activating the NRF2-SLC7A11 pathway and escaping from immune-mediated ferroptosis. Structural modeling and molecular docking analysis identified a functional inhibitor for SLC13A3 (SLC13A3i). Deletion of ACOD1 (an essential enzyme for itaconate synthesis) in macrophages, genetic ablation of SLC13A3 in tumors, or treatment with SLC13A3i sensitized tumors to ferroptosis, curbed tumor progression, and bolstered ICB effectiveness. Thus, we identify the interplay between tumors and TAMs via the SLC13A3-itaconate-NRF2-SLC7A11 axis as a previously unknown immune ferroptosis resistant mechanism in the TME and SLC13A3 as a promising immunometabolic target and disease indication for treating SLC13A3+cancer.
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| Overall design |
Yumm5.2 cells underwent treatment with permeable itaconate or DMSO reagent control and were cultured for 20 hours.
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| Contributor(s) |
Lin H, Tison K, Du Y |
| Citation missing |
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| Submission date |
May 24, 2024 |
| Last update date |
Sep 19, 2024 |
| Contact name |
Weiping Zou |
| E-mail(s) |
wzou@med.umich.edu, linheng@med.umich.edu, kolet@med.umich.edu
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| Organization name |
University of Michigan
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| Department |
Surgery
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| Lab |
Weiping Zou
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| Street address |
109 Zina Pitcher Pl
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| City |
Ann Arbor |
| State/province |
MI |
| ZIP/Postal code |
48109 |
| Country |
USA |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (8)
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| GSM8289292 |
DMSO, replicate 4, RNAseq |
| GSM8289293 |
4-OI, replicate 1, RNAseq |
| GSM8289294 |
4-OI, replicate 2, RNAseq |
| GSM8289295 |
4-OI, replicate 3, RNAseq |
| GSM8289296 |
4-OI, replicate 4, RNAseq |
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| Relations |
| BioProject |
PRJNA1116127 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE268293_gene_FPKM.annot.txt.gz |
1.5 Mb |
(ftp)(http) |
TXT |
| GSE268293_gene_TPM.annot.txt.gz |
1.5 Mb |
(ftp)(http) |
TXT |
| GSE268293_gene_expected_count.annot.txt.gz |
1.4 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
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