Targeting cancer stem cell plasticity and tumor microenvironment crosstalk: a comprehensive review

Cancer remains a major global health challenge, marked by profound heterogeneity and adaptability that frequently limit the success of conventional and targeted therapies. Among the diverse cellular populations within tumors, cancer stem cells (CSCs) have emerged as key drivers of initiation, progression, metastasis, and therapeutic resistance. Sharing core features with normal stem cells, including self-renewal and multipotency, CSCs sustain tumor growth and contribute to intratumoral heterogeneity. Importantly, the traditional hierarchical model has been revised with the recognition of CSC plasticity—the dynamic ability of cells to transition between CSC and non-CSC states or among distinct CSC subsets. This phenotypic flexibility, governed by intrinsic genetic and epigenetic mechanisms and strongly influenced by extrinsic cues from the tumor microenvironment (TME), underpins therapeutic resistance, immune evasion, and disease recurrence. The TME represents a complex, dynamic ecosystem composed of stromal cells, immune populations, extracellular matrix components, and soluble factors. Far from a passive scaffold, the TME actively engages in reciprocal crosstalk with CSCs, sustaining stemness, modulating plasticity, and shaping tumor progression. This bidirectional interplay reinforces CSC survival, fuels metastatic potential, and contributes to therapeutic failure. A comprehensive understanding of CSC plasticity and CSC–TME interactions is therefore essential for the design of durable therapeutic strategies. This review synthesizes current knowledge of the molecular and cellular mechanisms driving CSC plasticity and their microenvironmental regulation. It further evaluates emerging approaches—including small molecules, epigenetic modulators, and TME-normalizing therapies—that target these processes, and discusses challenges and future directions for translating these strategies into precision oncology.