TRIM21-mediated degradation of HILPDA overcomes anti-PD-1 immunotherapy resistance in breast cancer by limiting PD-L1 palmitoylation - PubMed
4 hours ago
- #PD-L1 palmitoylation
- #breast cancer
- #immunotherapy resistance
- HILPDA identified as a tumor-intrinsic regulator of immune evasion in breast cancer.
- HILPDA overexpression increases regulatory T cells and decreases CD8+ T cells and natural killer cells, creating an immunosuppressive tumor microenvironment.
- HILPDA binds to HSP90, protecting KLF5 from degradation, sustaining fatty acid synthesis and lipid droplet accumulation.
- Increased palmitate enhances PD-L1 palmitoylation, stabilizing PD-L1 and maintaining inhibitory signaling.
- TRIM21 mediates K63-linked polyubiquitination of HILPDA, promoting its degradation.
- Fenretinide engages TRIM21 to decrease PD-L1 palmitoylation, reprogramming the tumor microenvironment and improving anti-PD-1 efficacy.
- TRIM21/HILPDA-targeted combinations proposed as a therapeutic strategy to overcome ICB resistance.