Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance
Heng Lin, Kole Tison, Yuheng Du, Paul D. Kirchhoff, Chan Kim, Weichao Wang, Hannah Yang, Michael Pitter, Jiali Yu, Peng Liao, Jiajia Zhou, Linda Vatan, Sara Grove, Shuang Wei, Thomas M. Vigil, Yatrik M. Shah, Richard M. Mortensen, Ilona Kryczek, Lana X. Garmire, Jwala Priyadarsini Sivaccumar, Ashwin Ramesh, Ningyan Zhang, Zhiqiang An, Shaomeng Wang, Weiping Zou
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. • Tumor SLC13A3 expression correlates with ICB efficacy and patient survival • SLC13A3 is a transporter for itaconate in tumors • TAM-derived itaconate endows tumor ferroptosis resistance and progression • SLC13A3 inhibitor sensitizes tumor ferroptosis and treats ICB-resistant tumor In brief, Lin et al. demonstrate that SLC13A3 functions as an itaconate transporter, allowing tumor cells to uptake macrophage-derived itaconate through SLC13A3. This process contributes to tumor resistance to ferroptosis via the itaconate-NRF2-SLC7A11 axis. They also identify an SLC13A3 inhibitor (SLC13A3i) that enhances the efficacy of immunotherapy in preclinical mouse models.