Pitfalls and strategies of CAR-T therapy in solid tumors and implications for chordoma treatment.

In recent years, CAR-T cell therapy has emerged as a promising immunotherapeutic approach, demonstrating remarkable therapeutic efficacy in hematologic malignancies such as leukemia and lymphoma. However, its effectiveness in treating solid tumors remains limited, with challenges such as low response rates, poor therapeutic persistence, and high recurrence rates. The unique and complex immune microenvironment of solid tumors, characterized by a dense extracellular matrix, an abundance of immunosuppressive cells, and cytokines, is considered a major factor impeding CAR-T cell infiltration, antitumor activity, and persistence, significantly hindering the clinical potential of this therapy. To address these challenges, various strategies have been developed to optimize CAR-T cell functionality and adaptability. As a rare and highly complex solid tumor, chordoma presents with several challenges for CAR-T cell therapy, including the lack of tumor-specific antigens, rich extracellular matrix, and enrichment of immunosuppressive factors such as TGF-β. This review summarizes the key challenges and corresponding strategies to enhance CAR-T cell therapy in solid tumors, with a particular focus on underlying its therapeutic potential for the treatment of chordoma.