Azeez Sarkar Sardar, Yashooa Raya Kh, Smail Shukur Wasman, Salihi Abbas, Ali Azhin Saber, Mamand Sami, Janson Christer
Department of Medical Laboratory Technology, Soran Technical College, Erbil Polytechnic University, Erbil, Kurdistan Region, 44008, Iraq.
Department of Biology, College of Education for Pure Sciences, University of Al-Hamdaniya, Mosul, 41002, Iraq.
Mol Cancer. 2025 Jul 7;24(1):191. doi: 10.1186/s12943-025-02386-8.
Chimeric antigen receptor-cell therapies have demonstrated remarkable success in haematological malignancies but face significant hurdles in solid tumours. The hostile tumour microenvironment, antigen heterogeneity, limited tumour infiltration, and CAR-cell exhaustion contribute to reduced efficacy. Additionally, toxicity, off-target effects, and manufacturing challenges limit widespread clinical adoption. Overcoming these barriers requires a multifaceted approach that enhances CAR-cell persistence, trafficking, and tumour-specific targeting. Recent advancements in alternative cellular therapies, such as CAR-natural killer cells, CAR-macrophages, gamma delta CAR-T cells, and CAR-natural killer T cells, provide promising avenues for improving efficacy. These strategies leverage distinct immune cell properties to enhance tumour recognition and persistence. Furthermore, combination therapies, including chemotherapy, radiotherapy, antibodies, small molecule inhibitors, cancer vaccines, oncolytic viruses, and multi-CAR cell combination therapy, offer synergistic potential by modulating the TME and improving CAR-cell functionality. This review explores the challenges of CAR-based cellular therapies in solid tumours and highlights emerging strategies to overcome therapeutic limitations. By integrating novel cellular platforms and combination approaches, we seek to provide insights into optimising CAR-cell therapies for durable responses in solid malignancies.
嵌合抗原受体细胞疗法在血液系统恶性肿瘤中已显示出显著成效，但在实体瘤治疗中却面临重大障碍。恶劣的肿瘤微环境、抗原异质性、有限的肿瘤浸润以及嵌合抗原受体细胞耗竭，均导致疗效降低。此外，毒性、脱靶效应以及生产方面的挑战，限制了其在临床上的广泛应用。克服这些障碍需要采取多方面的方法，以增强嵌合抗原受体细胞的持久性、归巢能力以及肿瘤特异性靶向性。替代细胞疗法的最新进展，如嵌合抗原受体自然杀伤细胞、嵌合抗原受体巨噬细胞、γδ嵌合抗原受体T细胞以及嵌合抗原受体自然杀伤T细胞，为提高疗效提供了有前景的途径。这些策略利用不同免疫细胞的特性来增强肿瘤识别和持久性。此外，联合疗法，包括化疗、放疗、抗体、小分子抑制剂、癌症疫苗、溶瘤病毒以及多嵌合抗原受体细胞联合疗法，通过调节肿瘤微环境和改善嵌合抗原受体细胞功能，具有协同增效的潜力。本综述探讨了基于嵌合抗原受体的细胞疗法在实体瘤治疗中的挑战，并强调了克服治疗局限性的新兴策略。通过整合新型细胞平台和联合方法，我们旨在为优化嵌合抗原受体细胞疗法以在实体恶性肿瘤中实现持久缓解提供见解。
