Cancer-Derived Succinate Promotes Macrophage Polarization and Cancer Metastasis via Succinate Receptor

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. [Display omitted] •Cancer cells secrete succinate to promote TAM polarization and cancer metastasis•Cancer-cell-derived secreted succinate is related to reduction of SDH activity•SUCNR1-triggered PI3K-HIF-1α axis mediates TAM polarization and cancer metastasis•Serum succinate is elevated in patients with lung cancer and serves as a biomarker We have shown that cancer cells secrete succinate into extracellular milieu, which mediates TAM polarization and promotes cancer metastasis. Succinate exerts its effects on TAM polarization and cancer metastasis via a specific membrane receptor, SUCNR1, which transmits signaling through the PI3K/HIF-1α pathway.