ADA1-Driven Metabolic Refueling Enhances CAR T Cell Therapy for Solid Tumors

CAR T cell therapy, while highly effective for hematological malignancies, continues to face significant hurdles in the treatment of solid tumors. Key challenges include severe nutrient deprivation and the presence of immunosuppressive metabolites such as adenosine in the tumor microenvironment, which limit CAR T cell persistence and antitumor activity. This review focuses on current progress and future directions for ADA1-based metabolic reprogramming as a targeted approach to enhance CAR T cell function. We discuss recent advances, particularly the engineering of CAR T cells to express ADA1, which facilitates the local conversion of immunosuppressive adenosine into inosine, thereby supporting T cell metabolism and improving therapeutic outcomes. Preclinical studies, including our own, demonstrate that ADA1-expressing CAR T cells exhibit reduced exhaustion, greater metabolic flexibility, and enhanced antitumor efficacy in solid tumor models. The selective clearance of adenosine and supplementation of inosine directly address the metabolic barriers within the tumor microenvironment and provide an effective strategy to bolster CAR T cell responses. Integration of ADA1-driven metabolic refueling with future innovations in CAR design holds promise for overcoming key obstacles in solid tumor immunotherapy. We conclude by highlighting the potential of ADA1-based strategies and offering our perspective on their translation toward clinical application.