Next frontiers in systemic therapy for soft tissue sarcoma

Soft tissue sarcoma (STS) is a heterogeneous disease with more than 50 subtypes. Once the disease reached locally advanced or metastatic status, the standard treatment remains to be chemotherapy. Current understanding of the underlying molecular and genomic mechanisms of different histology subtypes have led to encouraging development of new drugs in treating STS. Besides molecular targeted therapy, immunotherapy have also shown promising advancement in solid tumor treatments. This review will be in two parts. The first part will focus on the molecular targeted agents aiming at molecular or genetic alterations that are more specific in STS, including antiangiogenic molecules, plate-derived growth factor receptor alpha (PDGFRA) monoclonal antibody, colony-stimulating factor-1 receptor (CSF-1R), selective inhibitors of nuclear export (SINE), cyclin-dependent kinase 4/6 (CDK 4/6), mdm2, and epigenetic regulators. We also discussed in depth about how current precision medicine influences the treatment paradigm in STS. In the second part, we focus on the landscape of immunotherapy in STS including immune checkpoint inhibitors (ICIs) and the combinations of immunotherapies or with other molecules that could modulate the tumor microenvironment. These included the program cell death-1 receptor and its ligand (PD-1/PD-L1), cytotoxic T lymphocyte associated protein-4 (CTLA-4) and the combination with anti-angiogenic agents that could facilitate the trafficking of T cells. Strategies targeting the tumor-associated antigen NY-ESO-1, which is commonly observed in synovial sarcoma and myxoid round cell liposarcoma, via viral vaccines and adoptive T cells will also be discussed. These new frontiers of treatment that are developed with better insights into sarcoma and immune biology hopefully will change the treatment paradigm of advanced STS in the future.