2. Academic Validation
  3. Itaconate transporter SLC13A3 confers immunotherapy resistance via alkylation-mediated stabilization of PD-L1

Itaconate transporter SLC13A3 confers immunotherapy resistance via alkylation-mediated stabilization of PD-L1

  • Cell Metab. 2025 Feb 4;37(2):514-526.e5. doi: 10.1016/j.cmet.2024.11.012.
Yizeng Fan 1,  Weichao Dan 1,  Yuzhao Wang 1,  Zhiqiang Ma 2,  Yanlin Jian 1,  Tianjie Liu 1,  Mengxing Li 1,  Zixi Wang 1,  Yi Wei 1,  Bo Liu 1,  Peng Ding 3,  Yuzeshi Lei 1,  Chendong Guo 1,  Jin Zeng 1,  Xiaolong Yan 3,  Wenyi Wei 4,  Lei Li 5
Affiliations

Affiliations

  • 1 Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China; Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi 710061, P.R. China.
  • 2 Department of Medical Oncology, Senior Department of Oncology, Chinese PLA General Hospital, The Fifth Medical Center, Beijing 100853, P.R. China.
  • 3 Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, Shaanxi 710038, P.R. China.
  • 4 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: wwei2@bidmc.harvard.edu.
  • 5 Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China; Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi 710061, P.R. China. Electronic address: lilydr@163.com.
PMID: 39809284 DOI: 10.1016/j.cmet.2024.11.012
Abstract

Itaconate is a metabolite catalyzed by cis-aconitate decarboxylase (ACOD1), which is mainly produced by activated macrophages and secreted into the extracellular environment to exert complex bioactivity. In the tumor microenvironment, itaconate is concentrated and induces an immunosuppressive response. However, whether itaconate can be taken up by tumor cells and its mechanism of action remain largely unclear. Here, we identified solute carrier family 13 member 3 (SLC13A3) as a key protein transporting extracellular itaconate into cells, where it elevates programmed cell death ligand 1 (PD-L1) protein levels and decreases the expression of immunostimulatory molecules, thereby promoting tumor immune evasion. Mechanistically, itaconate alkylates the cysteine 272 residue on PD-L1, antagonizing PD-L1 ubiquitination and degradation. Consequently, SLC13A3 inhibition enhances the efficacy of anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) immunotherapy and improves the overall survival rate in syngeneic mouse tumor models. Collectively, our findings identified SLC13A3 as a key transporter of itaconate and revealed its immunomodulatory role, providing combinatorial strategies to overcome immunotherapy resistance in tumors.

Keywords

IRG1; PD-L1; SLC13A3; immunotherapy; itaconate.

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