Arora Swati, Sethi Pranshul, Banerjee Adrita, Akanda Md Khokon Miah, Abd El Hafeez Mohamed S, Mehjabin Sanzia, Moharir Keshav S, Mohanty Swati, Sheoran Sumit
School of Agricultural Biotechnology, Punjab Agriculture University, Ludhiana, Punjab, India.
Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab 140401, India; Department of Pharmacology, College of Pharmacy, Shri Venkateshwara University, Gajraula, UP 244236, India.
Int Immunopharmacol. 2026 Jan 1;168(Pt 1):115838. doi: 10.1016/j.intimp.2025.115838. Epub 2025 Nov 14.
Chimeric Antigen Receptor T-cell (CAR-T) therapy has revolutionized cancer immunotherapy, achieving remarkable success in hematological malignancies. However, its clinical application to solid tumors is hindered by significant challenges, including tumor antigen heterogeneity, the immunosuppressive tumor microenvironment (TME), and physical barriers that limit effective T-cell infiltration. This review examines the intricate mechanisms of CAR-T therapy, with a focus on T-cell engineering, activation, and tumor targeting, highlighting the interplay between therapeutic design and tumor-specific complexities. The barriers unique to solid tumors, such as immune evasion mediated by suppressive cytokines and regulatory cells, tumor antigen escape, and the resilience of the extracellular matrix, are critically analyzed. Innovative strategies, including multi-antigen targeting constructs, logic-gated CARs for tumor-selective activation, and armored CAR-T cells equipped to counteract immunosuppressive signals, are evaluated for their potential to enhance therapeutic efficacy. Furthermore, the incorporation of matrix-degrading enzymes and immune checkpoint inhibitors is discussed as a means to overcome physical and immune-mediated resistance. Emerging targets such as B7-H3, Claudin 18.2, and MUC1, along with advancements in companion diagnostics, are reshaping the landscape of CAR-T therapy by enabling more precise patient selection and real-time therapeutic monitoring. This review synthesizes recent progress and persisting challenges, aiming to provide a comprehensive framework for advancing CAR-T therapy into a transformative modality for the treatment of solid tumors.
嵌合抗原受体T细胞（CAR-T）疗法彻底改变了癌症免疫疗法，在血液系统恶性肿瘤中取得了显著成功。然而，其在实体瘤中的临床应用受到重大挑战的阻碍，包括肿瘤抗原异质性、免疫抑制性肿瘤微环境（TME）以及限制有效T细胞浸润的物理屏障。本文综述探讨了CAR-T疗法的复杂机制，重点关注T细胞工程、激活和肿瘤靶向，强调了治疗设计与肿瘤特异性复杂性之间的相互作用。对实体瘤特有的障碍进行了批判性分析，如由抑制性细胞因子和调节性细胞介导的免疫逃逸、肿瘤抗原逃逸以及细胞外基质的韧性。评估了创新策略的潜力，包括多抗原靶向构建体、用于肿瘤选择性激活的逻辑门控CAR以及配备有对抗免疫抑制信号的装甲CAR-T细胞，以提高治疗效果。此外，还讨论了引入基质降解酶和免疫检查点抑制剂作为克服物理和免疫介导抗性的手段。诸如B7-H3、Claudin 18.2和MUC1等新兴靶点，以及伴随诊断的进展，正在通过实现更精确的患者选择和实时治疗监测来重塑CAR-T疗法的格局。本文综述综合了近期进展和持续存在的挑战，旨在为将CAR-T疗法推进成为治疗实体瘤的变革性模式提供一个全面的框架。
