FYN/LCK kinase balance as a metabolic switch orchestrates progenitor exhausted T Cell differentiation in hepatocellular carcinoma - PubMed
14 hours ago
- #T cell exhaustion
- #Immunotherapy
- #Hepatocellular carcinoma
- FYN/LCK kinase balance acts as a metabolic switch in progenitor exhausted T (Tpex) cell differentiation in hepatocellular carcinoma (HCC).
- FYN is identified as a marker of Tpex cells in immune checkpoint blockade (ICB) responders.
- FYN deficiency leads to LCK hyperactivation, causing terminal exhaustion in CD8+ T cells under high-affinity antigen stimulation.
- LCK hyperactivation disrupts metabolic homeostasis by increasing glycolysis and impairing mitochondrial function in Tpex cells.
- LCK inhibition restores FYN activity, improves mitochondrial fitness, and preserves Tpex cell stemness.
- Transient LCK inhibition during T cell expansion enhances adoptive cell therapy efficacy in preclinical HCC models.
- Preemptive low-dose LCK inhibition before anti-PD1 therapy expands Tpex cells, reduces terminal exhaustion, and improves outcomes.
- Modulating FYN/LCK balance is a promising strategy to overcome immunotherapy resistance in HCC.