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.
CAR-T细胞疗法在血液系统恶性肿瘤治疗中成效显著，但在实体瘤治疗中仍面临重大挑战。肿瘤微环境中严重的营养匮乏及免疫抑制性代谢物（如腺苷）的存在，限制了CAR-T细胞的持久性与抗肿瘤活性。本综述聚焦于基于ADA1的代谢重编程作为增强CAR-T细胞功能的靶向策略，探讨其当前进展与未来方向。我们重点论述了通过基因工程使CAR-T细胞表达ADA1的最新进展，该策略能促进免疫抑制性腺苷在局部转化为肌苷，从而支持T细胞代谢并改善治疗效果。临床前研究（包括我们团队的工作）表明，表达ADA1的CAR-T细胞在实体瘤模型中表现出耗竭程度降低、代谢适应性增强及抗肿瘤效能提升。腺苷的选择性清除与肌苷的补充直接针对肿瘤微环境中的代谢屏障，为增强CAR-T细胞应答提供了有效策略。将ADA1驱动的代谢重塑与未来CAR设计的创新相结合，有望突破实体瘤免疫治疗的关键障碍。最后，我们强调基于ADA1策略的潜力，并对其临床转化前景提出展望。
ADA1-Driven Metabolic Refueling Enhances CAR T Cell Therapy for Solid Tumors
肿瘤(癌症)患者之家