SS18-SSX drives TYK2 expression to activate STAT3/Bcl2 axis, facilitating apoptosis evasion and advancing synovial sarcoma progression

Synovial sarcoma (SS) is a rare soft tissue sarcoma characterized by high-grade malignancy and poor prognosis. Preliminary research indicates that apoptosis evasion is a key factor in SS progression, primarily attributed to the overexpression of anti-apoptotic genes. However, the mechanisms underlying this phenomenon are still not fully understood. This study aims to investigate the factors responsible for apoptosis evasion, evaluate their potential as targets for anti-apoptotic interventions, and analyze their mechanisms in detail. Our findings reveal that tyrosine kinase 2 (TYK2) is upregulated in highly malignant SS. Through in vitro as well as in vivo functional analyses, we have demonstrated that, TYK2 significantly accelerates SS cells progression. Mechanistically, TYK2 activates STAT3, which promotes the expression of BCL2 , an anti-apoptotic gene. Inhibition of STAT3 activation using specific inhibitors can disrupt the TYK2-enhanced expression of Bcl2, indicating that the TYK2/STAT3/Bcl2 axis is a key regulatory pathway mediating apoptosis evasion in SS. Furthermore, our investigation into the upstream regulation of TYK2 reveals that the fusion protein SS18-SSX enhances the transcriptional activity of TYK2 by binding to the promoter region of the TYK2 gene, thereby increasing its expression levels. Thus, the TYK2/STAT3/Bcl2 axis is a crucial mechanism through which SS18-SSX mediates apoptosis evasion in SS cells. In conclusion, our findings contribute to understanding how SS18-SSX-driven TYK2 expression mediates apoptosis evasion mechanisms and propose targeting TYK2 as a strategy to induce apoptosis in SS. Graphical Abstract