Epigenetic crosstalk between stem cells and tumors: mechanisms and emerging perspectives.

Abstract

Stem cells possess self-renewal and multipotent differentiation capabilities, exhibiting broad applications in regenerative medicine and tissue homeostasis maintenance. Their fate regulation relies heavily on precise epigenetic mechanisms. Cancer stem cells (CSCs), as key drivers of tumor heterogeneity, recurrence, and drug resistance, share extensive epigenetic features with normal stem cells, forming a complex and dynamic regulatory network. Mechanisms including DNA methylation, histone modification, chromatin remodeling, and ncRNAs collectively sustain stem cell pluripotency and tumor stemness, while aberrant epigenetic alterations serve as core drivers of tumor initiation and progression. In recent years, with the advent of single-cell omics and CRISPR-dCas9 epigenetic editing technologies, epigenetic "crosstalk" between stem cells and tumor cells has been progressively uncovered, especially the multidimensional epigenetic reprogramming induced by the tumor microenvironment (TME) that promotes CSC traits and drug resistance. This review systematically summarizes the epigenetic regulatory mechanisms of stem cells, epigenetic abnormalities in tumors, their interactions, and translational potential in therapeutic strategies, focusing on frontier topics such as reversible epigenetic plasticity, metabolic-epigenetic interplay, and liquid biopsy epigenetic biomarkers. Looking forward, artificial intelligence (AI) and big data analysis are expected to deepen the understanding of epigenetic heterogeneity, driving integrative innovations in precision medicine and regenerative interventions. Comprehensive understanding of the epigenetic crosstalk between stem cells and tumors will provide solid theoretical support and technical pathways for CSC-targeted therapies, epigenetic drug development, and stem cell fate manipulation.