肿瘤细胞治疗研究
英文原题：Tracing the development of CAR-T cell design: from concept to next-generation platforms.
嵌合抗原受体（CAR）-T细胞疗法通过利用适应性免疫系统选择性清除癌细胞，代表了癌症免疫治疗领域的一项变革性突破。
嵌合抗原受体（CAR）-T细胞疗法通过利用适应性免疫系统选择性清除癌细胞，代表了癌症免疫治疗领域的一项变革性突破。在血液系统恶性肿瘤治疗方面的开创性进展已促使FDA批准了多种CAR-T细胞疗法，尤其是针对复发或难治性疾病患者。这一成功得益于CAR结构的持续改进，从早期治疗效力有限的原型发展到整合了共刺激结构域、细胞因子信号传导、安全开关和精准控制机制的先进下一代受体。本综述阐明了CAR-T细胞开发的基本原理，并探讨了所遇到的关键生物学挑战。受体工程、代谢重编程和优化免疫信号传导方面的进展显著增强了CAR-T细胞的持久性、抗肿瘤活性和安全性。此外，新兴的基因工程工具，包括CRISPR、碱基编辑、先导编辑以及RNA和表观基因组编辑，有望降低免疫原性并最大限度减少移植物抗宿主病（GVHD）的风险。然而，CAR-T细胞疗法仍面临若干挑战，包括严重副作用如细胞因子释放综合征（CRS）和神经毒性、治疗反应不一致以及高昂的生产成本。为克服这些障碍，新型方法正在开发中，包括在体内生成CAR-T细胞、利用逻辑门控CAR系统，以及将CAR平台扩展至其他免疫效应细胞，如NK 细胞（CAR-NK）和巨噬细胞（CAR-M）。基于CAR的疗法的未来有望整合合成生物学、免疫检查点调控和创新递送方法，以提升治疗效果和安全性。本综述综合了当前知识和新兴策略，以指导未来进展，旨在将CAR疗法的适用性扩展至多种癌症类型及潜在的其他疾病。
Chimeric Antigen Receptor (CAR)-T cell therapy represents a transformative breakthrough in cancer immunotherapy by harnessing the adaptive immune system to selectively eradicate cancer cells. Pioneering advances in the treatment of hematological malignancies have led to the FDA approval of several CAR-T cell therapies, particularly for patients with relapsed or refractory disease. This success is a result of continuous refinements in CAR architecture, which have evolved from early prototypes with limited therapeutic efficacy to advanced next-generation receptors that incorporate co-stimulatory domains, cytokine signaling, safety switches, and precision control mechanisms. This review elucidates the fundamental rationale behind CAR-T cell development and addresses key biological challenges encountered. Advances in receptor engineering, metabolic reprogramming, and optimized immune signaling have markedly enhanced the persistence, antitumor activity, and safety profiles of CAR-T cells. Additionally, emerging genetic engineering tools, including CRISPR, base editing, prime editing, and RNA and epigenome editing, hold promise for reducing immunogenicity and minimizing the risk of graft-versus-host disease (GVHD). However, CAR-T cell therapy continues to face several challenges, including severe side effects such as cytokine release syndrome (CRS) and neurotoxicity, inconsistent therapeutic responses, and high production costs. To overcome these barriers, novel approaches are under development that include generating CAR-T cells in vivo , utilizing logic-gated CAR systems, and expanding CAR platforms to include other immune effector cells, such as natural killer cells (CAR-NK) and macrophages (CAR-M). The future of CAR-based therapies is expected to integrate synthetic biology, immune checkpoint modulation, and innovative delivery methods to enhance both therapeutic efficacy and safety. This review synthesizes current knowledge and emerging strategies to guide future advancements aimed at expanding the applicability of CAR therapy to various cancer types and potentially other diseases.
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