Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance.

Cancer Cell

Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Graduate Program in Cancer Biology, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Published: December 2024

AI Article Synopsis

  • Immune checkpoint blockade (ICB) can induce tumor ferroptosis, but many patients don't respond because tumors evade this process within the tumor microenvironment (TME).
  • Researchers found that SLC13A3 acts as a transporter for itaconate in tumor cells, contributing to resistance against ferroptosis, which weakens tumor immunity and reduces ICB effectiveness.
  • Targeting SLC13A3 through various methods, like genetic alteration or using a specific inhibitor, can sensitize tumors to ferroptosis, slow down tumor growth, and enhance the effectiveness of ICB treatments, highlighting SLC13A3 as a potential target for cancer therapy.

Article Abstract

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 discover 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 identify 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 sensitize tumors to ferroptosis, curb tumor progression, and bolster 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 for treating SLC13A3 cancer.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11631639PMC
http://dx.doi.org/10.1016/j.ccell.2024.10.010DOI Listing

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