Language
English
Publication Date
12-9-2024
Journal
Cancer Cell
DOI
10.1016/j.ccell.2024.10.010
PMID
39515327
PMCID
PMC11631639
PubMedCentral® Posted Date
12-9-2025
PubMedCentral® Full Text Version
Author MSS
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
Ferroptosis, Animals, Humans, Mice, Tumor Microenvironment, NF-E2-Related Factor 2, Succinates, Cell Line, Tumor, Tumor-Associated Macrophages, Amino Acid Transport System y+, Mice, Inbred C57BL, Neoplasms, Female, Carboxy-Lyases, Hydro-Lyases, NRF2, SLC13A3, SLC13A3 inhibitor, SLC7A11, T cell immunity, ferroptosis, immune checkpoint blockade, itaconate, macrophages, tumor
Published Open-Access
yes
Recommended Citation
Lin, Heng; Tison, Kole; Du, Yuheng; et al., "Itaconate Transporter SLC13A3 Impairs Tumor Immunity via Endowing Ferroptosis Resistance" (2024). The Brown Foundation: Institute of Molecular Medicine. 9.
https://digitalcommons.library.tmc.edu/molecular_med/9