The efficacy of stem cell therapy: cells or their microenvironment?

The therapeutic outcomes of stem cell therapy are determined not solely by cellular potency alone, but also by the receptiveness of the host microenvironment. Despite continuous progress in stem cell quality control and functional optimization technologies, inconsistent outcomes remain prevalent in the clinical application of stem cell therapy across different disease contexts. This inconsistency gives rise to a crucial question: Does the efficacy of stem cell therapy depend on the implanted cells themselves or their microenvironment? Accumulating evidence suggests that the microenvironment, composed of immune, metabolic, and structural components, serves as a critical contributing factor. They collectively influence regenerative success or failure. Concurrently, this review discusses innovative approaches and strategies developed to address the current limitations of stem cell therapy, including targeted molecular interventions, engineered biomaterial scaffolds, synergistic co-transplantation strategies, and the therapeutic application of stem cell-derived exosomes. Furthermore, this review explores key frontier research directions in the field of stem cell therapy, covering the development of high-fidelity disease models, precision medicine based on patient stratification, the bidirectional engineering of cells and their cellular niche, and the challenge of promoting regeneration while suppressing oncogenesis. We argue that achieving clinical efficacy for stem cell therapies in degenerative diseases and injuries necessitate a paradigm shift. Specifically, future therapeutic strategies will likely need to transition from relying solely on simple cell delivery to the precise reconstruction of the regenerative niche.