USP14-mediated deubiquitination of SIRT1 in macrophage promotes fatty acid oxidation amplification and M2 phenotype polarization

There is a trend of increasing young cases with gastric cancer globally. Sensitive early diagnosis methods and new therapeutic approaches are still the focus of clinical diagnosis and therapy of gastric cancer. USP14 plays an extensive role in tumor malignancy and fat metabolism regulation. However, researchers still have gaps in their knowledge of its substrates, which makes it difficult for deubiquitinases to become clinical targets. TAMs were isolated from tumor or polarized from primary THP1 cells by tumors cell lines under the control of IU1 and FAO inhibitor therapy. Cytokines controlled macrophages were compared to evaluate the capability to induce USP14 expression. Fatty acid uptake assay and OCR measurement were used to analyze macrophage metabolism. USP14 is found the correlation with tumor poor prognosis and poor immunophenotype in gastric cancer patients and mouse tumor models. Activation of USP14 determines elevated protein stability of SIRT1 and is required for activation of macrophage fatty acid oxidation and immunosuppressive phenotype. Although overexpression of USP14 is not sufficient to polarize macrophages to the M2 phenotype, inhibition of USP14 by IU1 in tumor-bearing mice disrupts the suppressive activity of cancer-promoting macrophages and effectively reshapes immune microenvironment characteristics. Our study provides evidence that a novel therapeutic strategy that targets to lipid metabolism of macrophages in tumors could be a potential option for emerging treatments for gastric cancer.