SLC3A2 Promotes Tumor Associated Macrophage Polarization via Metabolic Reprogramming in Lung Cancer.

Tumor associated macrophages (TAMs) are one of the most abundant immunosuppressive cells in the tumor microenvironment and possess crucial functions in facilitating tumor progression. Emerging evidences indicate that altered metabolic properties in cancer cell support the tumorigenic functions of TAMs. However, mechanisms and mediators underly crosstalk between cancer cell and TAMs remain largely unknown. In present study, we revealed that high Solute Carrier Family 3 Member 2 (SLC3A2) expression in lung cancer patients were associated with TAMs and poor prognosis. Knockdown of SLC3A2 in lung adenocarcinoma cells impaired M2 polarization of macrophages in co-culture system. By using metabolome analysis, we identified that knockdown SLC3A2 altered metabolism of lung cancer cells and changed multiple metabolites including arachidonic acid in the tumor microenvironment. More importantly, we demonstrated that arachidonic acid was responsible for SLC3A2 mediated macrophage polarization in the tumor microenvironment to differentiate into M2 type both in vitro and in vivo. Our data illustrate previously undescribed mechanisms responsible for TAMs polarization and suggest that SLC3A2 acts as a metabolic switch on lung adenocarcinoma cells to induce macrophage phenotypic reprogramming via arachidonic acid.