Cancer Heterogeneity and Cancer Cell Plasticity: Molecular Mechanisms and Precision Therapy

Tumor heterogeneity creates selective pressures and ecological niches that enable cancer cell plasticity; conversely, plasticity continuously generates and reshapes heterogeneity. Together, these processes drive tumor progression, therapeutic resistance, recurrence, and divergent clinical outcomes, thereby limiting the durability of precision oncology. In this Review, we synthesize recent advances in our understanding tumor heterogeneity and cancer cell plasticity across spatial, temporal, and molecular scales, and discuss how the tumor microenvironment regulates plasticity through physical, chemical, and biological cues. We further outline three fundamental challenges for precision therapy, namely, target loss, bypass pathway activation, and adaptive cell-state transitions, and argue that drug resistance is critically shaped by cancer cell plasticity, which varies widely among patients and contributes to heterogeneous therapeutic efficacy. Building on this framework, we propose a next-generation precision-oncology paradigm integrating stratified diagnosis, rational combination intervention, and adaptive monitoring. Finally, we discuss how the integration of single-cell and spatial multiomics, together with artificial intelligence, could enable the development of "digital twin" tumor models to guide individualized therapeutic decision-making. Collectively, this review provides an integrated conceptual foundation and practical roadmap for overcoming key bottlenecks in precision oncology driven by tumor heterogeneity and cancer cell plasticity.