The evolution of cellular therapies in sarcoma: Breakthroughs, challenges, and future directions

Cellular therapies representa promising area of immunotherapy for advanced cancers,therapies including T cell receptor (TCR) therapies, chimeric antigen receptor (CAR) T cell therapies, tumor-infiltrating lymphocyte (TIL) therapies, and natural killer (NK) cell therapies.Sarcomas pose unique challenges due to their molecular complexity and immunosuppressive tumor microenvironment (TME). TCRtherapiesargeting antigens likeNY-ESO-1, MAGE-A4, and PRAME have shown efficacy, highlighted by the FDA's accelerated approval of afamitresgene autoleucel targeting MAGE-A4 for synovial sarcoma.CAR-T cell therapies targeting HER2, GD2, and B7-H3, along with TIL, and NK cell therapies are also under investigation.However, many are in early stages of clinical development, and their effectiveness may vary by sarcoma subtype. Overcoming challenges such as immunosuppressive TME, antigen escape, lack of T-cell persistence, and off-target toxicities is crucial to improving outcomes for sarcoma patients. This review summarizes the evolution of cellular therapies,ongoing research, challenges, and future directions in this field.