Escobar Giulia, Berger Trisha R, Maus Marcela V
Krantz Family Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA; Cellular Immunotherapy Program, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA; Harvard Medical School, Boston, MA, USA.
Krantz Family Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA; Cellular Immunotherapy Program, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
Cell Rep Med. 2025 Nov 18;6(11):102353. doi: 10.1016/j.xcrm.2025.102353. Epub 2025 Sep 12.
Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies, but its efficacy in solid tumors is limited by several challenges. Key obstacles include insufficient CAR-T cell trafficking to tumors, limited expansion and persistence, tumor relapse due to antigen loss or heterogeneity, and an immunosuppressive tumor microenvironment (TME) that dampens CAR-T cell functions. In this review, we discuss insights from recent successful clinical trials in advanced solid tumors and highlight groundbreaking strategies integrating synthetic biology and gene engineering to enhance CAR-T cell fitness, potency, and persistence, activate host immunity, reprogram the TME, and enable multi-antigen targeting. We examine strengths and weaknesses of current preclinical models for assessing the efficacy and safety of CAR-T cell therapies, including human xenografts in immunodeficient mice and humanized or syngeneic models. The array of cutting-edge approaches employed in next-generation CAR-T cell therapies is expected to transform the treatment landscape of solid tumors.
嵌合抗原受体（CAR）-T细胞疗法彻底改变了血液系统恶性肿瘤的治疗方式，但其在实体瘤治疗中的疗效受到诸多挑战的限制。主要障碍包括CAR-T细胞向肿瘤部位的归巢不足、扩增和持久性受限、因抗原丢失或异质性导致的肿瘤复发，以及抑制CAR-T细胞功能的免疫抑制性肿瘤微环境（TME）。在这篇综述中，我们讨论了近期晚期实体瘤成功临床试验的见解，并强调了整合合成生物学和基因工程的开创性策略，以提高CAR-T细胞的适应性、效力和持久性，激活宿主免疫，重编程TME，并实现多抗原靶向。我们研究了当前用于评估CAR-T细胞疗法疗效和安全性的临床前模型的优缺点，包括免疫缺陷小鼠中的人源异种移植模型以及人源化或同基因模型。预计下一代CAR-T细胞疗法中采用的一系列前沿方法将改变实体瘤的治疗格局。
