近日，西安交通大学李磊等研究人员合作发现，衣康酸转运蛋白SLC13A3通过烷基化介导的PD-L1稳定性赋予免疫治疗抗性。2025年1月13日，国际知名学术期刊《细胞—代谢》在线发表了这一成果。

研究人员鉴定了溶质载体家族13成员3（SLC13A3）作为将细胞外衣康酸运输到细胞内的关键蛋白。在细胞内，衣康酸可提高程序性死亡配体1（PD-L1）蛋白水平并降低免疫刺激分子的表达，从而促进肿瘤免疫逃逸。机制上，衣康酸通过烷基化PD-L1上的半胱氨酸272位点，对抗PD-L1的泛素化和降解。结果表明，抑制SLC13A3可增强抗CTLA-4（细胞毒性T淋巴细胞相关抗原-4）免疫治疗的疗效，并改善同系小鼠肿瘤模型的总体生存率。

总体而言，该研究确定了SLC13A3作为衣康酸关键转运蛋白的作用，并揭示了其免疫调节功能，为克服肿瘤免疫治疗抗性提供了联合治疗策略。

据悉，衣康酸是一种由顺乌头酸脱羧酶（ACOD1）催化生成的代谢产物，主要由活化的巨噬细胞产生并分泌到细胞外环境中以发挥复杂的生物活性。在肿瘤微环境中，衣康酸被浓缩并诱导免疫抑制反应。然而，衣康酸是否能被肿瘤细胞摄取及其作用机制尚不明确。

附：英文原文

Title: Itaconate transporter SLC13A3 confers immunotherapy resistance via alkylation-mediated stabilization of PD-L1

Author: Yizeng Fan, Weichao Dan, Yuzhao Wang, Zhiqiang Ma, Yanlin Jian, Tianjie Liu, Mengxing Li, Zixi Wang, Yi Wei, Bo Liu, Peng Ding, Yuzeshi Lei, Chendong Guo, Jin Zeng, Xiaolong Yan, Wenyi Wei, Lei Li

Issue&Volume: 2025-01-13

Abstract: Itaconate is a metabolite catalyzed by cis-aconitate decarboxylase (ACOD1), which is mainly produced by activated macrophages and secreted into the extracellular environment to exert complex bioactivity. In the tumor microenvironment, itaconate is concentrated and induces an immunosuppressive response. However, whether itaconate can be taken up by tumor cells and its mechanism of action remain largely unclear. Here, we identified solute carrier family 13 member 3 (SLC13A3) as a key protein transporting extracellular itaconate into cells, where it elevates programmed cell death ligand 1 (PD-L1) protein levels and decreases the expression of immunostimulatory molecules, thereby promoting tumor immune evasion. Mechanistically, itaconate alkylates the cysteine 272 residue on PD-L1, antagonizing PD-L1 ubiquitination and degradation. Consequently, SLC13A3 inhibition enhances the efficacy of anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) immunotherapy and improves the overall survival rate in syngeneic mouse tumor models. Collectively, our findings identified SLC13A3 as a key transporter of itaconate and revealed its immunomodulatory role, providing combinatorial strategies to overcome immunotherapy resistance in tumors.

DOI: 10.1016/j.cmet.2024.11.012

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00480-7