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

作者：Lao M, Zhang X, Li Z, Sun K, Yang H, Wang S, He L, Chen Y, Zhang H, Shi J, Xu D, Liang T, Bai X · 发表于：Cancer communications (London, England) · 年份：2025 · DOI：10.1002/cac2.70038 · 研究领域：PCSK9、PD‐1/PD‐L1、Pancreatic ductal adenocarcinoma、SREBP1、immunochemotherapy、immunosuppressive tumor microenvironment、lipid metabolism

BACKGROUND: Pancreatic cancer's aberrant lipid metabolism fuels cell growth, invasion, and metastasis, yet its impact on immune surveillance and immunotherapy is unclear. This study investigated how sterol regulatory element-binding transcription factor 1 (SREBP1)-driven lipid metabolism affects the tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC). METHODS: Clinical significance of SREBP1 was assessed in a PDAC cohort from China and The Cancer Genome Atlas (TCGA) cohorts. The in vitro mechanisms that SREBP1 regulated programmed cell death-ligand 1 (PD-L1) and proprotein convertase subtilisin/kexin type 9 (PCSK9) were investigated using immunofluorescence, flow cytometry, Western blotting, luciferase assays and chromatin immunoprecipitation. In vivo studies using PDAC-bearing mice, humanized patient-derived tumor xenograft (PDX) models, and autochthonous model of mutation (GEMM-KTC) evaluated the efficacy and mechanisms of programmed death receptor 1 (PD-1) antibodies and lipid inhibitors. RESULTS: Patients responding to anti-PD-1 therapy exhibited lower serum lipid levels than non-responders. Targeting SREBP1 disrupted lipid metabolism, decelerated tumor growth, and boosted the efficacy of immunotherapy for PDAC. Mechanistically, SREBP1 directly bound the PD-L1 promoter, suppressing its transcription. Meanwhile, PCSK9, a direct transcriptional target of SREBP1, modulated PD-L1 levels via lysosomal degradation. Consequently, the combination of PCSK9-ne...