Pancreatic ductal adenocarcinoma (PDAC) is characterized by marked fibrosis and low immunogenicity, features that are linked to treatment resistance and poor clinical outcomes. Therefore, understanding how PDAC regulates the desmoplastic and immune stromal components is of great clinical importance. We found that acyl-CoA synthetase long-chain 3 (ACSL3) is up-regulated in PDAC and correlates with increased fibrosis. Our in vivo results show that Acsl3 knockout hinders PDAC progression, markedly

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... reduces tumor fibrosis and tumor-infiltrating immunosuppressive cells, and increases cytotoxic T cell infiltration. This effect is, at least in part, due to decreased plasminogen activator inhibitor-1 (PAI-1) secretion from tumor cells. Accordingly, PAI-1 expression in PDAC positively correlates with markers of fibrosis and immunosuppression and predicts poor patient survival. We found that PAI-1 pharmacological inhibition strongly enhances chemo-and immunotherapeutic response against PDAC, increasing survival of mice. Thus, our results unveil ACSL3-PAI-1 signaling as a requirement for PDAC progression with druggable attributes. RESULTS ACSL3 is up-regulated in human PDAC To assess the expression level of ACSL3 in human pancreatic cancer, we examined publicly available human patient-derived data from the Gene Expression Omnibus (GEO) database (subset GSE71729). Our analysis evidenced that the mRNA level of ACSL3 is higher in primary ductal adenocarcinomas and metastasis compared to healthy epithelium (Fig. 1A) . These results were additionally confirmed with paired analysis from matched healthy and PDAC human samples (dataset GSE62452), showing a marked increase in the expression of ACSL3 compared to adjacent healthy tissue from the same patients (Fig. 1B) .