Cell and gene therapies using haematopoietic stem cells (HSCs) epitomize the transformative potential of regenerative medicine. Recent clinical successes for gene therapies involving autologous HSC transplantation (HSCT) demonstrate the potential of genetic engineering in this stem cell type for curing disease. With recent advances in CRISPR gene-editing technologies, methodologies for the ex vivo expansion of HSCs and non-genotoxic conditioning protocols, the range of clinical indications for HSC-based gene therapies is expected to significantly expand. However, substantial immunological challenges need to be overcome. These include pre-existing immunity to gene-therapy reagents, immune responses to neoantigens introduced into HSCs by genetic engineering, and unique challenges associated with next-generation and off-the-shelf HSC products. By synthesizing these factors in this Review, we hope to encourage more research to address the immunological issues associated with current and next-generation HSC-based gene therapies to help realize the full potential of this field.

使用造血干细胞（HSC）的细胞和基因疗法体现了再生医学的变革潜力。最近涉及自体造血干细胞移植（HSCT）的基因疗法的临床成功证明了基因工程在这种干细胞类型中治疗疾病的潜力。随着 CRISPR 基因编辑技术、HSC 离体扩增方法和非基因毒性调理方案的最新进展，基于 HSC 的基因疗法的临床适应症范围预计将显着扩大。然而，需要克服大量的免疫学挑战。其中包括对基因治疗试剂的现有免疫力、对通过基因工程引入 HSC 的新抗原的免疫反应，以及与下一代和现成的 HSC 产品相关的独特挑战。通过在这篇综述中综合这些因素，我们希望鼓励更多的研究来解决与当前和下一代基于 HSC 的基因疗法相关的免疫学问题，以帮助实现该领域的全部潜力。