Macrophages form a major cell population in the tumor microenvironment. They can be activated and polarized into tumor-associated macrophages (TAM) by the tumor-derived soluble molecules to promote tumor progression and metastasis. Here, we used comparative metabolomics coupled with biochemical and animal studies to show that cancer cells release succinate into their microenvironment and activate succinate receptor (SUCNR1) signaling to polarize macrophages into TAM. Furthermore, the results from in vitro and in vivo studies revealed that succinate promotes not only cancer cell migration and invasion but also cancer metastasis. These effects are mediated by SUCNR1-triggered PI3K-hypoxia-inducible factor 1α (HIF-1α) axis. Compared with healthy subjects and tumor-free lung tissues, serum succinate levels and lung cancer SUCNR1 expression were elevated in lung cancer patients, suggesting an important clinical relevance. Collectively, our findings indicate that the secreted tumor-derived succinate belongs to a novel class of cancer progression factors, controlling TAM polarization and promoting tumorigenic signaling.

中文翻译：

---

癌症衍生的琥珀酸酯通过琥珀酸酯受体促进巨噬细胞极化和癌症转移。

巨噬细胞在肿瘤微环境中形成主要的细胞群。它们可以被肿瘤来源的可溶性分子激活并极化为肿瘤相关的巨噬细胞（TAM），从而促进肿瘤的进展和转移。在这里，我们将比较代谢组学与生化和动物研究相结合，以显示癌细胞将琥珀酸释放到其微环境中并激活琥珀酸受体（SUCNR1）信号传导，使巨噬细胞极化为TAM。此外，体外和体内研究的结果表明，琥珀酸酯不仅促进癌细胞的迁移和侵袭，而且还促进癌症的转移。这些作用是由SUCNR1触发的PI3K低氧诱导因子1α（HIF-1α）轴介导的。与健康受试者和无肿瘤的肺组织相比，肺癌患者的血清琥珀酸水平和肺癌SUCNR1表达升高，提示其重要的临床意义。总的来说，我们的发现表明，分泌的肿瘤来源的琥珀酸酯属于一类新的癌症进展因子，可控制TAM极化并促进致瘤信号。