Kamli Hossam, Khan Najeeb Ullah
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, 61421, Abha, Saudi Arabia.
Institute of Biotechnology and Genetic Engineering, The University of Agriculture, Peshawar, 25130, Pakistan.
Med Oncol. 2025 May 31;42(7):228. doi: 10.1007/s12032-025-02783-5.
Chimeric Antigen Receptor T-cell (CAR-T) therapy represents a groundbreaking advance in oncology, leveraging patient-specific immune cells to target malignant tumours precisely. By equipping T cells with synthetic receptors, CAR-T therapy achieves remarkable antitumor effects and offers hope for durable cancer control. However, several limitations persist, including antigen scarcity, immunosuppressive tumour microenvironments, and T-cell exhaustion. CRISPR-Cas9 gene editing has enhanced CAR-T potency by knocking out immune checkpoints (PD-1, CTLA-4) and improving persistence, while RNA interference (RNAi) silences immune-evasion genes (e.g. SOCS1). Nanozyme-based delivery systems enable precise CRISPR-Cas9 delivery (> 70% editing efficiency) and tumour targeting, overcoming instability and off-target effects. Innovations like SUPRA CARs, armoured CAR-T cells (e.g. IL-12/IL-21-secreting TRUCKs), and dual checkpoint inhibition synergize to reprogram the tumour microenvironment, reducing relapse by 40% in trials. Despite progress, high costs, manufacturing hurdles, and ethical concerns (e.g. germline editing risks) remain critical barriers. Emerging solutions include universal off-the-shelf CAR-Ts, hybrid nano-CRISPR systems, and AI-driven design, paving the way for scalable, personalised immunotherapy. This review highlights breakthroughs in CRISPR, RNAi, and nanotechnology, underscoring CAR-T therapy's transformative potential while addressing translational challenges for broader clinical adoption.
嵌合抗原受体T细胞（CAR-T）疗法是肿瘤学领域的一项突破性进展，它利用患者特异性免疫细胞精确靶向恶性肿瘤。通过为T细胞配备合成受体，CAR-T疗法取得了显著的抗肿瘤效果，并为持久控制癌症带来了希望。然而，仍然存在一些局限性，包括抗原稀缺、免疫抑制性肿瘤微环境和T细胞耗竭。CRISPR-Cas9基因编辑通过敲除免疫检查点（PD-1、CTLA-4）和提高持久性增强了CAR-T的效力，而RNA干扰（RNAi）则使免疫逃逸基因（如SOCS1）沉默。基于纳米酶的递送系统能够实现CRISPR-Cas9的精确递送（编辑效率>70%）和肿瘤靶向，克服了不稳定性和脱靶效应。诸如SUPRA CARs、武装CAR-T细胞（如分泌IL-12/IL-21的TRUCKs）和双重检查点抑制等创新措施协同作用，对肿瘤微环境进行重新编程，在试验中将复发率降低了40%。尽管取得了进展，但高成本、生产障碍和伦理问题（如生殖系编辑风险）仍然是关键障碍。新兴的解决方案包括通用现成的CAR-T细胞、混合纳米CRISPR系统和人工智能驱动的设计，为可扩展的个性化免疫疗法铺平了道路。这篇综述强调了CRISPR、RNAi和纳米技术方面的突破，强调了CAR-T疗法的变革潜力，同时也解决了更广泛临床应用中的转化挑战。
