Pancreatic ductal adenocarcinoma (PDAC) is notoriously resistant to immunotherapy. Researchers at Zhejiang University discovered that the lipid metabolism regulator SREBP1 drives immune evasion in PDAC by directly suppressing PD-L1 transcription while simultaneously activating PCSK9, which stabilizes PD-L1 through lysosomal degradation pathways. Patients responding to anti-PD-1 therapy had significantly lower serum lipid levels than non-responders. Targeting SREBP1 and combining PCSK9-neutralizing antibodies with PD-1 blockade produced robust anti-tumor responses in humanized patient-derived xenograft models and spontaneous genetically engineered mouse models, suggesting a clinically actionable strategy to sensitize pancreatic cancer to immunochemotherapy.
