Cell Reprogramming: Therapeutic Advances and Challenges.

Abstract

Cell reprogramming, which forcibly alters cell fate, offers a novel therapeutic strategy for various refractory diseases. Unlike previous reviews focused on a single disease context or a single reprogramming modality, this review is organized around therapeutic applications. It summarizes advances in direct reprogramming, partial reprogramming, and cell fusion-induced reprogramming and further compares their mechanisms, challenges in clinical translation, and safety boundaries. In oncology, reprogramming cancer cells into antigen-presenting cells elicits durable antitumor immunity and remodels the tumor microenvironment, whereas converting cancer cells into nonmalignant somatic cells can reduce their malignant phenotype and tumorigenic potential. In neurodegenerative diseases, direct reprogramming has converted fibroblasts or astrocytes into functional dopaminergic and cortical neurons both in vitro and in vivo. In mouse models of progeria and natural aging, partial reprogramming strategies markedly extend lifespan, ameliorate multiorgan pathology, and enhance tissue regenerative capacity. However, the strength and reproducibility of these findings vary across experimental models, and reported therapeutic benefits do not necessarily establish complete, stable, or safe cell-fate conversion. Against this predominantly preclinical background, ER-100 is the first regenerative therapy based on partial epigenetic reprogramming to receive Food and Drug Administration Investigational New Drug approval and enter clinical testing. It therefore provides an important reference point for the transition from animal studies to human trials. Cell fusion-induced reprogramming has context-dependent roles in tumor immunity. Fusion between tumor cells and immune cells may promote malignant progression. In contrast, dendritic cell-tumor cell fusion vaccines and chimeric exosomes can activate antitumor immune responses in preclinical models and early clinical studies. Major barriers to clinical translation include low reprogramming efficiency, an incompletely defined safety window, and the need to select in vivo or ex vivo strategies according to disease context. In addition, insufficient delivery efficiency, poor targeting, and long-term tumorigenic risk remain important constraints on clinical application. Looking ahead, single-cell multiomics and artificial intelligence may help optimize reprogramming factor combinations, while nonviral systems may improve targeted delivery. Integration with tissue engineering may further facilitate clinical translation across oncology, aging, regenerative medicine, autoimmune diseases, and neuropsychiatric disorders.