Lipid metabolism reprograming by SREBP1-PCSK9 targeting sensitizes pancreatic cancer to immunochemotherapy

Pancreatic ductal adenocarcinoma (PDAC) treatment is challenging. Determining the metabolic pathways that regulate lipids will provide new insights into PDAC therapeutic strategies. Sterol regulatory element binding transcription factor 1 (SREBP-1) regulates multiple cancer pathways; however, its role in the tumor immune microenvironment and cancer immunotherapy is unknown. Herein, we integrated our large PDAC cohort data and identified that SREBP-1, as a master transcriptional regulator of lipogenesis, aggravated lipid metabolism reprogramming in PDAC. Furthermore, interrupting lipid metabolism by targeting SREBP-1 suppressed PDAC cell growth and enhanced antitumor immunity in vitro and in vivo. We demonstrated that SREBP-1 binds to the PD-L1 (programmed cell death 1 ligand 1) promoter to suppress its transcription. Importantly, SREBP-1 binds to the PCSK9 (proprotein convertase subtilisin/kexin type 9) promoter, which regulated PD-L1 levels via lysosome-mediated degradation and aggravated tumor microenvironment immunosuppression. Targeting the SREBP-1- PCSK9 axis using available drugs sustained the remission of aggressive PDAC by synergizing with anti-PD-1 and gemcitabine. In summary, targeting lipid metabolism suppressed tumor growth and relieved tumor immunosuppression in PDAC. RNA-seq profiling of wildtype KPC and PANC02 cells and their knockdown derivatives (shSrebf1)