Lipid metabolism reprograming by SREBP1-PCSK9 targeting sensitizes pancreatic cancer to immunochemotherapy [CUT&Tag]

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.