Cancer Communications | Targeting the SREBP1-PCSK9 axis enhances the efficacy of pancreatic cancer immunotherapy

This study reveals the potential application of targeting the SREBP1-PCSK9 axis in pancreatic cancer immunotherapy, offering a novel strategy to reverse resistance to immune checkpoint inhibitors.

 

Literature Overview

This article, titled 'Lipid metabolism reprogramming by SREBP1-PCSK9 targeting sensitizes pancreatic cancer to immunochemotherapy,' published in the journal Cancer Communications, reviews and summarizes the relationship between lipid metabolism and immune microenvironment regulation in pancreatic cancer. It focuses on the role of the SREBP1-PCSK9 signaling axis in regulating PD-L1 expression and immune evasion, as well as its mechanism in enhancing anti-PD-1 therapy.

Background Knowledge

Pancreatic ductal adenocarcinoma (PDAC) is a highly resistant malignancy, and its immunosuppressive tumor microenvironment (TME) is a major reason for the limited efficacy of immune checkpoint blockade (ICB) therapy. According to the tumor immune microenvironment (TIME) classification, most PDAC patients fall into the non-inflamed category (Type I and Type IV), characterized by low PD-L1 expression and sparse tumor-infiltrating lymphocytes (TILs), which restricts the effectiveness of ICB. Lipid metabolism plays a critical role in cancer cell proliferation and immune cell function regulation; however, its mechanisms in PDAC immune evasion remain unclear. This study investigates how targeting SREBP1 and its downstream effector PCSK9 can modulate PD-L1 expression and improve anti-PD-1 therapy response. The study also involves gene-edited cell lines, mouse models, and multi-omics analyses to validate the link between lipid metabolism and immune therapy response.

 

 

Research Methods and Experiments

The research team assessed the clinical significance of SREBP1 in a PDAC patient cohort. Using techniques such as immunofluorescence, flow cytometry, Western blot, dual-luciferase reporter assays, and chromatin immunoprecipitation (ChIP), they analyzed the regulatory mechanisms of SREBP1 on PD-L1 and PCSK9. In vitro experiments employed gene knockout, overexpression, and RNA interference to investigate the impact of SREBP1 on lipid metabolism and PD-L1 expression. In vivo experiments utilized KPC, PANC02, GEMM-KTC, and humanized PDX models to evaluate the combined efficacy of PD-1 antibodies and lipid metabolism inhibitors. Metabolomic and proteomic analyses revealed the signaling pathways affected by the SREBP1-PCSK9 axis, while flow cytometry and multiplex immunohistochemistry (mIHC) were used to examine changes in immune cell infiltration.

Key Conclusions and Perspectives

• SREBP1 directly binds to the PD-L1 promoter and suppresses its transcription, leading to reduced PD-L1 protein levels.
• PCSK9, as a downstream target of SREBP1, regulates PD-L1 stability via the lysosomal degradation pathway.
• Genetic silencing or pharmacological inhibition of SREBP1 significantly reduces lipid metabolism in PDAC cells and enhances CD8+ T cell infiltration and function.
• Combination treatment with lipid metabolism inhibitors (e.g., Fatostatin) and PD-1 antibodies markedly suppresses PDAC tumor growth.
• In a high-fat diet (HFD) model, SREBP1 inhibition reverses the immunosuppressive TME and enhances ICB efficacy.
• Targeting SREBP1 or PCSK9 can convert a non-inflammatory TIME into an inflammatory one, thereby improving the response rate to anti-PD-1 therapy in PDAC.

Research Significance and Prospects

This study provides a new combined metabolic-immunological strategy for PDAC treatment. Targeting SREBP1 or PCSK9 not only modulates lipid metabolism but also enhances immunotherapeutic responses by improving T cell activity. Future studies should explore the clinical translational potential of combining PCSK9-neutralizing antibodies with PD-1 inhibitors, as well as their applicability in other tumor types.

 

 

Conclusion

In summary, this study systematically analyzed the role of the SREBP1-PCSK9 signaling axis in PDAC immune evasion, revealing a post-transcriptional regulatory mechanism between lipid metabolism and PD-L1 expression. Targeting this axis effectively reverses PDAC resistance to ICB therapy, offering a promising treatment strategy for pancreatic cancer patients. These findings expand the theoretical framework of metabolic regulation in PDAC and provide experimental evidence for clinical combination immunotherapy, holding significant translational medicine value.

 

Mengyi Lao, Xiaozhen Zhang, Zejun Li, Tingbo Liang, and Xueli Bai. Lipid metabolism reprogramming by SREBP1-PCSK9 targeting sensitizes pancreatic cancer to immunochemotherapy. Cancer Communications.