Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance

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: wzou@umich.edu.

PMID: 39515327
PMCID: PMC11631639 (available on 2025-12-09)
DOI: 10.1016/j.ccell.2024.10.010

Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance

Heng Lin et al. Cancer Cell. 2024.

. 2024 Dec 9;42(12):2032-2044.e6.

doi: 10.1016/j.ccell.2024.10.010. Epub 2024 Nov 7.

Authors

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: wzou@umich.edu.

PMID: 39515327
PMCID: PMC11631639 (available on 2025-12-09)
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.

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Conflict of interest statement

Declaration of interests W.Z. serves as a scientific advisor or consultant for Cstone, Hanchor Bio, and NextCure. S. Wang is a consultant for Proteovant Therapeutics and owns stock in Roivant Sciences. S. Wang is a co-founder, paid consultant, and member of the board of directors of Ascentage Pharma Group International and owns stock in Ascentage. N.Z., Z.A., J.P.S., A.K.R., W.Z., H.L., S. Wang, and P.K. are listed inventors in a patent application (UTSH.P0407US.P1) related to this work.

References

1. Zou W, Wolchok JD, & Chen L (2016). PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Science translational medicine, 8(328), 328rv4. - PMC - PubMed
1. Kalbasi A, & Ribas A (2020). Tumour-intrinsic resistance to immune checkpoint blockade. Nature reviews. Immunology, 20(1), 25–39. - PMC - PubMed
1. Pitt JM, Marabelle A, Eggermont A, Soria JC, Kroemer G, & Zitvogel L (2016). Targeting the tumor microenvironment: removing obstruction to anticancer immune responses and immunotherapy. Annals of oncology: official journal of the European Society for Medical Oncology, 27(8), 1482–1492. - PubMed
1. Zou W, & Green DR (2023). Beggars banquet: Metabolism in the tumor immune microenvironment and cancer therapy. Cell metabolism, 35(7), 1101–1113. - PMC - PubMed
1. Chapman NM, & Chi H (2022). Metabolic adaptation of lymphocytes in immunity and disease. Immunity, 55(1), 14–30. - PMC - PubMed

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Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance

Affiliations

Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases