Histone lactylation-driven feedback loop modulates cholesterol-linked immunosuppression in pancreatic cancer
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View abstract on PubMed
Summary
This summary is machine-generated.Histone lactylation drives pancreatic cancer progression by promoting cholesterol metabolism and immune suppression. Targeting this pathway with ACAT2 degradation enhances anti-PD-1 therapy response.
Area Of Science
- Cancer Epigenetics
- Tumor Microenvironment
- Metabolic Reprogramming
Background
- Pancreatic cancer shows poor response to immunotherapy due to its immunosuppressive microenvironment.
- Lactate-driven histone lactylation's role in pancreatic cancer TME is underexplored.
Purpose Of The Study
- Investigate histone lactylation in pancreatic cancer.
- Determine its effects on cholesterol metabolism and anti-tumor immunity.
Main Methods
- Global lactylome profiling, RNA sequencing, CUT&Tag, IP-MS, GST-pull down.
- Mass cytometry, in vitro co-culture, orthotopic models, flow cytometry to study ACAT2.
- Development of an ACAT2-targeting PROTAC.
Main Results
- Lactate-driven histone lactylation (H3K18la) upregulates ACAT2.
- ACAT2 stabilizes MTCH2, disrupts oxidative phosphorylation, increasing lactate production.
- This creates a feedback loop involving cholesterol delivery via sEVs, promoting M2 macrophage polarization.
Conclusions
- The H3K18la/ACAT2/sEV-cholesterol axis is crucial for TME reprogramming in pancreatic cancer.
- Targeting this axis offers a novel strategy to enhance anti-PD-1 therapy response.
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