The Krebs cycle byproduct itaconate has recently emerged as an important metabolite regulating macrophage immune functions, but its role in tumor cells remains unknown. Here, we show that increased tumor-intrinsic cis-aconitate decarboxylase (ACOD1 or CAD, encoded by immune-responsive gene 1, Irg1) expression and itaconate production promote tumor immunogenicity and anti-tumor immune responses. Furthermore, we identify thimerosal, a vaccine preservative, as a specific inducer of IRG1 expression in tumor cells but not in macrophages, thereby enhancing tumor immunogenicity. Mechanistically, thimerosal induces itaconate production through a ROS-RIPK3-IRF1 signaling axis in tumor cells. Further, increased IRG1/itaconate upregulates antigen presentation-related gene expression via promoting TFEB nuclear translocation. Intratumoral injection of thimerosal induced itaconate production, activated the tumor immune microenvironment, and inhibited tumor growth in a T cell-dependent manner. Importantly, IRG1 deficiency markedly impaired tumor response to thimerosal treatment. Furthermore, itaconate induction by thimerosal potentiates the anti-tumor efficacy of adoptive T-cell therapy and anti-PD1 therapy in a mouse lymphoma model. Hence, our findings identify a new role for tumor intrinsic IRG1/itaconate in promoting tumor immunogenicity and provide a translational means to increase immunotherapy efficacy.

中文翻译：

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衣康酸盐的癌细胞固有生物合成促进肿瘤免疫原性。


克雷布斯循环副产物衣康酸盐最近成为调节巨噬细胞免疫功能的重要代谢物，但其在肿瘤细胞中的作用仍然未知。在这里，我们表明肿瘤内源性顺乌头酸脱羧酶 （ACOD1 或 CAD，由免疫反应基因 1， Irg1） 编码的表达和衣康酸盐的产生增加促进肿瘤免疫原性和抗肿瘤免疫反应。此外，我们确定疫苗防腐剂硫柳汞是 IRG1 在肿瘤细胞中表达的特异性诱导剂，但在巨噬细胞中没有，从而增强肿瘤免疫原性。从机制上讲，硫柳汞通过肿瘤细胞中的 ROS-RIPK3-IRF1 信号轴诱导衣康酸盐的产生。此外，IRG1/衣康酸盐的增加通过促进 TFEB 核转位上调抗原呈递相关基因表达。瘤内注射硫柳汞诱导衣康酸盐产生，激活肿瘤免疫微环境，并以 T 细胞依赖性方式抑制肿瘤生长。重要的是，IRG1 缺陷显着损害了肿瘤对硫柳汞治疗的反应。此外，硫柳汞诱导的衣康酸盐增强了小鼠淋巴瘤模型中过继性 T 细胞疗法和抗 PD1 疗法的抗肿瘤疗效。因此，我们的研究结果确定了肿瘤内在 IRG1/衣康酸盐在促进肿瘤免疫原性中的新作用，并提供了一种提高免疫治疗疗效的转化手段。