Cell-based immunotherapy is a promising treatment strategy for cancer. Particularly in the case of solid tumors, however, this strategy only benefits a minority of patients. A critical limitation to immunotherapy is T cell exhaustion, a terminal differentiation state characterized by loss of self-renewal and cytotoxic capacity. For over a decade, regenerative immunology approaches to overcome exhaustion and restore stem-like features of T cells have been pursued. The reprogramming of tumor-specific T cells back to a less-differentiated, stem-like state using induced pluripotent stem cell (iPSC) technology has been viewed as a powerful and highly appealing strategy to overcome the limitations imposed by exhaustion. However, clinical translation of these approaches has been stymied by the requirement for subsequent iPSC-to-T cell re-maturation strategies, vanishingly low efficiencies, and resource-intensive cell culture protocols. In this review, we discuss the emergence of transcription factor reprogramming to iPSCs, contemporary techniques for T cell reprogramming, as well as techniques for re-differentiation into mature T cells. We discuss the potential clinical utility of T cell reprogramming and re-maturation strategies alongside progress and major roadblocks toward clinical translation. If these challenges can be addressed, transcription factor reprogramming of T cells into iPSCs and subsequent re-maturation into tumor-specific stem-like T cells may represent an incredibly efficacious approach to cancer immunotherapy.
基于细胞的免疫疗法是一种极具前景的癌症治疗策略。然而，在实体瘤治疗中，该策略仅能使少数患者获益。免疫疗法面临的关键限制在于T细胞耗竭——这是一种以自我更新能力和细胞毒性功能丧失为特征的终末分化状态。十余年来，研究者们持续探索通过再生免疫学方法克服T细胞耗竭、恢复其干细胞样特性。利用诱导多能干细胞技术将肿瘤特异性T细胞重编程为分化程度较低的干细胞样状态，被视为突破耗竭限制的强大且极具吸引力的策略。但此类方法的临床转化面临多重阻碍：需要后续的iPSC向T细胞再成熟策略、极低的重编程效率以及资源密集型的细胞培养方案。本综述系统探讨了转录因子重编程技术向iPSC领域的发展、当代T细胞重编程技术，以及向成熟T细胞再分化的方法。我们深入分析了T细胞重编程与再成熟策略的临床转化潜力，同时梳理了该领域的研究进展与主要障碍。若能突破这些技术瓶颈，通过转录因子将T细胞重编程为iPSC并再分化为肿瘤特异性干细胞样T细胞，有望成为癌症免疫治疗中极具效力的创新策略。
Regenerative Immunotherapy for Cancer: Transcription Factor Reprogramming of Tumor-Specific T Cells
肿瘤(癌症)患者之家