Molecular and epigenetic oncogenesis in synovial sarcoma: implications for cancer biology, diagnosis and treatment

The SS18::SSX oncogene is the driver of synovial sarcoma, an aggressive cancer presenting in young adults that has poor long-term outcomes. Over the past five years, significant progress has been made in understanding the molecular, genomic, and epigenetic mechanisms underlying synovial sarcoma. This review synthesizes recent advancements in synovial sarcoma, including diagnostic pathology, genomic profiling, SS18::SSX biology, epigenetic dysregulation, proteomics, targetable pathways and immunotherapy. Key findings include the identification of rare but instructive alternative gene fusions, the roles of PRC1 and of liquid-liquid phase separation in SS18::SSX-mediated oncogenesis, and the development of epigenetic and engineered T-cell therapies. These advances offer new hope for improved treatments and outcomes in synovial sarcoma patients, though challenges remain in overcoming resistance and ensuring equitable access to emerging therapies.