Premchandani Tanvi, Qutub Mohammad, Tatode Amol, Umekar Milind, Taksande Jayshree, Hussain Ujban Md, Khidkikar Sameer R
Department of Pharmaceutics, Bhoyar College of Pharmacy, Smt. Kishoritai, Kamptee, Nagpur, Maharashtra, India.
Department of Pharmaceutical Sciences, Rashtrasant Tukdoji Maharaj Nagpur University, Nagpur, Maharashtra, India.
Immunol Res. 2025 Sep 20;73(1):135. doi: 10.1007/s12026-025-09687-6.
Chimeric antigen receptor T (CAR-T) cell therapy has revolutionized the treatment of hematologic malignancies, yet its efficacy in solid tumors remains limited due to antigen heterogeneity, immunosuppressive tumor microenvironments, and therapy-associated toxicities. This review highlights advances across CAR-T generations, emphasizing co-stimulatory domains and cytokine-armed TRUCKs to enhance persistence and function. Viral (lentiviral, gamma-retroviral) and non-viral (CRISPR, transposons, mRNA electroporation) delivery systems are compared for efficiency, safety, and scalability, with CRISPR enabling multiplex edits for improved specificity. Dual-targeting CARs counter antigen heterogeneity, while hypoxia-inducible and SynNotch CARs restrict activity to tumor sites. Chemokine receptor engineering enhances infiltration, and armored CARs secreting IL-12 or checkpoint inhibitors remodel the TME. Nanobody-based CAR-T cells further expand design versatility, offering improved stability, tumor penetration, and reduced immunogenicity compared with single-chain variable fragment constructs. Safety innovations include iCasp9 Suicide switches, dasatinib-controlled activation, and cytokine blockade. Clinical trials of bispecific CAR-Ts show promise, yet challenges Like manufacturing complexity and off-target effects persist. Integrating AI-driven design and Personalized neoantigen targeting may unlock CAR-T 2.0 for solid tumors, pending scalable production and regulatory harmonization.
嵌合抗原受体T（CAR-T）细胞疗法彻底改变了血液系统恶性肿瘤的治疗方式，然而由于抗原异质性、免疫抑制性肿瘤微环境以及治疗相关毒性，其在实体瘤治疗中的疗效仍然有限。本综述重点介绍了各代CAR-T的进展，强调共刺激结构域和细胞因子武装的TRUCKs以增强持久性和功能。对病毒（慢病毒、γ-逆转录病毒）和非病毒（CRISPR、转座子、mRNA电穿孔）递送系统的效率、安全性和可扩展性进行了比较，CRISPR能够进行多重编辑以提高特异性。双靶点CAR可对抗抗原异质性，而缺氧诱导型和SynNotch CAR将活性限制在肿瘤部位。趋化因子受体工程增强浸润，而分泌IL-12或检查点抑制剂的武装CAR重塑肿瘤微环境。基于纳米抗体的CAR-T细胞进一步扩展了设计的多功能性，与单链可变片段构建体相比，具有更高的稳定性、肿瘤穿透性和更低的免疫原性。安全创新包括iCasp9自杀开关、达沙替尼控制的激活和细胞因子阻断。双特异性CAR-T的临床试验显示出前景，但诸如制造复杂性和脱靶效应等挑战仍然存在。在可扩展生产和监管协调之前，整合人工智能驱动的设计和个性化新抗原靶向可能会解锁用于实体瘤的CAR-T 2.0。
