Cell plasticity in cancer and therapy resistance

Abstract Cancer cell plasticity, the ability of tumor cells to switch between distinct cellular states, has emerged as a key mechanism driving tumor progression, metastasis and therapy resistance. Cancer cells exploit diverse plasticity mechanisms, including dedifferentiation, transdifferentiation, epithelial–mesenchymal transition and stem cell-like reprogramming, to adapt to changes in their microenvironment or therapeutic pressures. These transitions are orchestrated by signaling pathways, epigenetic modifications and microenvironmental cues. Notably, plasticity encompasses reversible transitions among intermediate states that enhance metastatic potential and contribute to therapeutic failure. Tumor cells can enter drug-tolerant reversible states, enabling survival during treatment and leading to relapse. Recent advances in single-cell and spatial transcriptomics, along with conceptual frameworks such as the Waddington landscape, have provided new insights into the dynamic regulation of tumor cell-state transitions at high resolution. In this Review, we discuss the molecular and cellular mechanisms governing cancer cell plasticity, its impact on metastasis and therapy resistance, and recent technological advances that illuminate dynamic tumor cell-state transitions.