Major mechanisms of tumor plasticity and their roles in therapy resistance.
| Plasticity mechanism | Biological process | Key regulators and pathways | Representative tumor types | Therapeutic implications |
|---|---|---|---|---|
| Cancer stem cell (CSC) plasticity | Dynamic interconversion between stem-like and differentiated tumor cell states, allowing tumor cells to regain tumor-initiating capacity and therapy resistance | Developmental signaling pathways (Wnt/β-catenin, Notch, Hedgehog), stress-response transcription factors, chromatin remodeling programs [33, 34] | Breast cancer, glioblastoma, colorectal cancer, pancreatic cancer | Promotes tumor regeneration after therapy and contributes to relapse; targeting stemness signaling pathways may suppress tumor re-initiation |
| Phenotypic switching (EMT/MET and related programs) | Reversible transitions between epithelial, mesenchymal, and intermediate states enabling adaptation to environmental stress and therapeutic pressure | EMT transcription factors (SNAIL, TWIST, ZEB), transforming growth factor beta (TGF-β) signaling, MAPK signaling, transcriptional stress programs [35, 36] | Breast cancer, melanoma, lung cancer | Enhances invasiveness, metastatic potential, and tolerance to targeted therapies and chemotherapy |
| Lineage plasticity and transdifferentiation | Tumor cells adopt alternative lineage identities distinct from their original differentiation program, often under therapeutic pressure | Transcription factor reprogramming, epigenetic remodeling, loss of lineage-defining regulators [37, 38] | EGFR-mutant lung adenocarcinoma transitioning to small-cell phenotype; prostate adenocarcinoma transitioning to neuroendocrine prostate cancer; melanoma dedifferentiation | Enables tumors to bypass therapies targeting lineage-specific pathways and signaling dependencies |
| Epigenetic state switching | Large-scale transcriptional reprogramming driven by chromatin remodeling and enhancer landscape changes without permanent genetic mutation | Chromatin remodeling complexes, histone modifiers, enhancer rewiring, transcription factor network reorganization [39, 40] | Multiple tumor types including melanoma, glioblastoma, and breast cancer | Facilitates rapid adaptive responses to therapy and contributes to reversible drug-tolerant states |
| Microenvironment-driven plasticity | Extrinsic signals from the tumor microenvironment drive phenotypic transitions and adaptive tumor cell states | Hypoxia signaling (HIF pathways), inflammatory cytokines, stromal growth factors, extracellular matrix signaling [41, 42] | Solid tumors including pancreatic cancer, lung cancer, and colorectal cancer | Microenvironmental signals promote survival, stemness, and therapy resistance; targeting tumor-stroma interactions may disrupt adaptive plasticity |
EGFR: epidermal growth factor receptor; EMT: epithelial-mesenchymal transition; MAPK: mitogen-activated protein kinase; MET: mesenchymal-epithelial transition.
During the preparation of this work, the authors used OpenAI image-generation tools to assist with the initial preparation of conceptual figure drafts. After utilizing the tool, the authors reviewed, revised, and finalized the figures as necessary and take full responsibility for the final content of the publication.
OAAE: Investigation, Writing—original draft. MMN: Conceptualization, Investigation, Writing—original draft, Writing—review & editing, Supervision. Both authors read and approved the submitted version.
The authors declare that they have no conflicts of interest.
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