Cancer stem cell plasticity: mechanisms, immune microenvironment crosstalk, and therapeutic implications

Cancer stem cells (CSCs) represent functionally defined and phenotypically plastic tumor cell populations implicated in therapeutic resistance, relapse, and metastasis. CSC plasticity is regulated through coordinated stemness signaling and epigenetic mechanisms. Canonical stemness-associated pathways, including Wnt, Notch, and Hedgehog, interact with epigenetic programs to maintain dynamic stem-like states and facilitate cellular adaptation to environmental and therapeutic stress. These regulatory networks are also associated with metabolic reprogramming and may support CSC survival under therapeutic and immune pressure. This review summarizes recent advances in our understanding of CSC plasticity, with a particular focus on the bidirectional interplay between CSCs and the tumor immune microenvironment. From a translational perspective, it further summarizes emerging strategies for targeting CSC plasticity in combination with immunotherapy, and discusses the present limitations and challenges of combination strategies. These observations may provide a conceptual framework for the development of more rational combination strategies, although their clinical benefit remains to be validated.