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. 2025 Aug;45(8):1010-1037.
doi: 10.1002/cac2.70038. Epub 2025 May 29.

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

Mengyi Lao  1   2   3   4 , Xiaozhen Zhang  1   2   3 , Zejun Li  1   2   3 , Kang Sun  1   2   3 , Hanshen Yang  1   2   3 , Sicheng Wang  1   2   3 , Lihong He  1   2   3 , Yan Chen  1   2   3 , Hanjia Zhang  1   2   3 , Jiatao Shi  1   2   3 , Daqian Xu  1   2   5 , Tingbo Liang  1   2   3 , Xueli Bai  1   2   3
Affiliations

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

Mengyi Lao et al. Cancer Commun (Lond). 2025 Aug.

Abstract

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-neutralizing antibodies with PD-1 monotherapy showed a robust antitumor effect in both humanized PDX and GEMM-KTC models.

Conclusions: The SREBP1-PCSK9 axis-mediated lipid metabolism is crucial for triggering immune evasion and resistance to anti-PD-1. Targeting the SREBP1-PCSK9 axis could potentially reverse PDAC's resistance to anti-PD-1 therapy.

Keywords: PCSK9; PD‐1/PD‐L1; Pancreatic ductal adenocarcinoma; SREBP1; immunochemotherapy; immunosuppressive tumor microenvironment; lipid metabolism.

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References

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