Intratumoral heterogeneity: Biological basis, clinical impact and the emerging theory of tumor plasticity (Review)

Intratumoral heterogeneity (ITH) is a central feature of cancer biology and a major obstacle to effective long-term treatment; it encompasses the presence of diverse cellular subpopulations within a single tumor or across metastatic sites, differing at the genetic, epigenetic, transcriptional, metabolic and phenotypic levels.This diversity fuels tumor evolution, promotes immune evasion, facilitates metastasis and drives resistance to therapy.Recent technological advances, including next-generation sequencing, single-cell multi-omics, spatial transcriptomics and liquid biopsies, have revealed tumors as dynamic and adaptive ecosystems shaped by clonal competition and interactions with the tumor microenvironment.In addition to clonal evolution, tumor plasticity has emerged as a key mechanism, allowing cancer cells to reversibly shift between functional states (such as stem-like, proliferative, invasive, mesenchymal and drug-tolerant) without requiring new genetic mutations.This adaptability notably contributes to treatment failure and disease recurrence.The biological basis of ITH involves genomic instability, epigenetic alterations, cancer stem cells and microenvironmental influences.Both spatial and temporal heterogeneity further complicate diagnosis and treatment, as tumor composition evolves and varies across regions.Current evidence suggests that integrating comprehensive molecular profiling with longitudinal monitoring could enable adaptive, personalized therapeutic strategies.