Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance 2251

Abstract Description 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. Funding Sources This work was supported in part by research grants from the NIH/NCI grants for W. Z. (CA248430, CA217648, CA123088, CA099985, CA193136, and CA152470), Y.S. (R01CA148828 and CA245546), the NIH through the University of Michigan Rogel Cancer Center Support Grant (P30CA46592), and from the Welch Foundation for Z.A. (AU-0042-20030616). Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)