Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance

Heng Lin; Kole Tison; Yuheng Du; Paul Kirchhoff; Chan Kim; Weichao Wang; Hannah Yang; Michael Pitter; Jiali Yu; Peng Liao; Jiajia Zhou; Linda Vatan; Sara Grove; Shuang Wei; Thomas Vigil; Yatrik M Shah; Richard Mortensen; Ilona Kryczek; Lana Garmire; Jwala P Sivaccumar; Ashwin Kumar Ramesh; Ningyan Zhang; Zhiqiang An; Shaomeng Wang; Weiping Zou

doi:10.1016/j.ccell.2024.10.010

Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance

Cancer Cell. 2024 Nov 1:S1535-6108(24)00398-2. doi: 10.1016/j.ccell.2024.10.010. Online ahead of print.

Authors

Heng Lin¹, Kole Tison², Yuheng Du³, Paul Kirchhoff⁴, Chan Kim⁵, Weichao Wang¹, Hannah Yang⁵, Michael Pitter¹, Jiali Yu¹, Peng Liao¹, Jiajia Zhou¹, Linda Vatan¹, Sara Grove¹, Shuang Wei¹, Thomas Vigil⁶, Yatrik M Shah⁶, Richard Mortensen⁷, Ilona Kryczek¹, Lana Garmire³, Jwala P Sivaccumar⁸, Ashwin Kumar Ramesh⁸, Ningyan Zhang⁸, Zhiqiang An⁸, Shaomeng Wang⁹, Weiping Zou¹⁰

Affiliations

¹ 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.
² 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; Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, USA.
³ Department of Computational Medicine & Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA.
⁴ Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
⁵ 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 Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, South Korea.
⁶ Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
⁷ Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA.
⁸ Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁹ Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Medicinal Chemistry, University of Michigan Medical School, Ann Arbor, MI, USA.
¹⁰ 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: [email protected].

PMID: 39515327
DOI: 10.1016/j.ccell.2024.10.010

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.

Keywords: NRF2; SLC13A3; SLC13A3 inhibitor; SLC7A11; T cell immunity; ferroptosis; immune checkpoint blockade; itaconate; macrophages; tumor.