CAFs promote immune evasion in gastric cancer through histone lactylation-mediated suppression of NCAPG ubiquitination
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View abstract on PubMed
Summary
This summary is machine-generated.Cancer-associated fibroblasts (CAFs) promote gastric cancer (GC) progression and immune evasion via lactate secretion. This study identifies the H3K18la-ASPM-NCAPG axis and a potential inhibitor, Daturilin, to enhance anti-PD-1 therapy.
Area Of Science
- Oncology
- Cancer Biology
- Immunotherapy
Background
- Cancer-associated fibroblasts (CAFs) are key players in tumor progression and immune evasion.
- CAFs are a major source of lactate in the tumor microenvironment, influencing cancer.
- The role of CAF-derived lactate in gastric cancer (GC) immunotherapy is not well understood.
Purpose Of The Study
- To investigate the role of CAFs-derived lactate in gastric cancer progression and immune evasion.
- To elucidate the molecular mechanisms linking lactate to anti-PD-1 resistance in GC.
- To identify potential therapeutic targets for enhancing immunotherapy.
Main Methods
- CUT&Tag and transcriptome sequencing to identify histone lactylation targets.
- Co-immunoprecipitation, mass spectrometry, and molecular docking to study protein interactions.
- In vitro, in vivo, and organoid experiments to validate the proposed mechanism.
Main Results
- Elevated lactate from CAFs induced H3K18 lactylation (H3K18la) in GC cells.
- ASPM, a target of H3K18la, promotes GC progression and anti-PD-1 resistance.
- The ASPM-NCAPG interaction upregulates NCAPG expression via the SRC/STAT3 pathway, increasing PD-L1 levels.
- Daturilin identified as a potential small-molecule inhibitor of NCAPG.
Conclusions
- CAFs-derived lactate promotes GC progression through the H3K18la-ASPM-NCAPG axis.
- This axis contributes to immune evasion and resistance to anti-PD-1 therapy.
- Daturilin shows potential to improve anti-PD-1 treatment efficacy in GC.
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