美国密歇根大学Weiping Zou研究小组发现，伊曲康酸转运蛋白SLC13A3通过赋予铁死亡抗性来损害肿瘤免疫。2024年11月7日，《癌细胞》杂志在线发表了这项成果。

研究人员发现，SLC13A3是肿瘤细胞中的伊曲康酸转运蛋白，并赋予肿瘤铁死亡抗性，从而削弱肿瘤免疫和免疫检查点抑制（ICB）疗效。从机制上讲，肿瘤细胞通过SLC13A3从肿瘤相关巨噬细胞（TAM）摄取伊曲康酸，从而激活NRF2-SLC7A11通路，逃避免疫介导的铁死亡。

结构建模和分子对接分析识别出SLC13A3的功能抑制剂（SLC13A3i）。在巨噬细胞中删除ACOD1（伊曲康酸合成的关键酶）、在肿瘤中基因敲除SLC13A3或使用SLC13A3i治疗，可以使肿瘤对铁死亡更加敏感，抑制肿瘤进展并增强ICB疗效。

因此，研究人员发现肿瘤与TAM通过SLC13A3-伊曲康酸-NRF2-SLC7A11轴相互作用，作为肿瘤微环境（TME）中一种未知的免疫铁死亡抗性机制。且SLC13A3是治疗SLC13A3⁺癌症的有前景的免疫代谢靶点。

据介绍，ICB触发肿瘤铁死亡。然而，大多数患者对ICB无反应。肿瘤可能在TME中逃避铁死亡。

附：英文原文

Title: Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance

Author: 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

Issue&Volume: 2024-11-07

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.

DOI: 10.1016/j.ccell.2024.10.010

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00398-2