Tumor transition phases during therapy: biological features, biomarkers, and therapeutic implications.
| Transition phase | Biological features | Representative mechanisms | Candidate biomarkers and readouts | Therapeutic implications |
|---|---|---|---|---|
| Therapy-impact phase (early shock response) | Acute treatment response; rapid stress signaling; apoptosis in sensitive fraction; early survival programs in a subset [219] | DNA damage response; acute reactive oxygen species (ROS) surge; stress kinase activation; proteotoxic stress; early feedback rebound signaling [14] | Early ctDNA drop kinetics; acute stress-response transcriptional signatures; phospho-signaling changes; imaging response dynamics (early metabolic change) [220] | Identify early nonresponders; exploit immediate stress liabilities; initiate early combinations to prevent entry into tolerance/persistence [14, 220] |
| Plasticity phase | Increased phenotypic flexibility; reversible identity shifts; stem-like or slow-cycling programs; lineage instability [38, 174] | Transcriptional reprogramming; EMT/MET-like programs; lineage switching; chromatin remodeling; enhancer reconfiguration [221, 222] | Single-cell state shifts (scRNA-seq); chromatin accessibility dynamics (scATAC-seq); stemness/lineage signatures; enhancer activity patterns; methylation-based state signatures [139, 221] | Limit state exploration; target regulators of reprogramming; prioritize interventions that reduce plasticity and prevent commitment into resistant phenotypes [38, 221] |
| Persistence phase (drug-tolerant persisters) | Small surviving subpopulation; reversible tolerance; quiescent/slow-cycling behavior; minimal-residual-like state; stress-adapted phenotype [12, 84] | Epigenetic adaptation; altered proteostasis/UPR; metabolic rewiring; survival pathway dependence; anti-apoptotic programs [18, 223] | Detection of rare tolerant states by single-cell profiling; minimal residual disease signals; stress-response expression programs; survival pathway activation profiles; longitudinal ctDNA plateau/slow clearance [84, 220] | Target persister dependencies; combine tolerability-targeting with vulnerability targeting; prevent persisters from serving as reservoirs for stable resistance [13, 14] |
| Vulnerability phase (adaptive fragility) | Transitional fragility during reorganization; narrow pathway dependence; high stress burden; incomplete compensatory programs [218] | Therapy-induced metabolic stress; signaling rewiring; proteotoxic stress; heightened DNA repair reliance; collateral sensitivity; treatment-induced synthetic lethality [223, 224] | Metabolic stress indicators; ROS/redox markers; UPR signatures; dynamic phospho-signaling profiles; DNA repair activation signatures; imaging of hypoxia/metabolic shifts; ctDNA rebound kinetics suggesting adaptation [220, 223] | Best window for timed sequential/combination therapy; exploit newly essential pathways; target stress handling, repair dependencies, or compensatory signaling nodes before stabilization [14, 218] |
| Microenvironmental remodeling phase | Therapy-altered ecology; inflammatory signaling shifts; stromal/immune remodeling; niche support for survival states; spatial heterogeneity of response [225] | Hypoxia-driven programs; cytokine signaling; cancer-associated fibroblast (CAF)-mediated protection; immune editing; therapy-induced inflammation; altered vascular/ECM dynamics [226] | Spatial imaging changes (perfusion/hypoxia); cytokine/chemokine profiles; immune infiltration signatures; stromal activation markers; spatial transcriptomics readouts [225, 227] | Combine tumor-cell targeting with microenvironment-directed strategies; prevent niche-assisted persistence and resistance stabilization; guide region-specific interventions [228, 229] |
| Stabilization phase (durable resistance) | Consolidation of resistant phenotype; reduced reversibility; dominance of resistant clones; stable resistant transcriptional state [171, 230] | Secondary target mutations; pathway reactivation mutations; gene amplification; bypass pathway activation; epigenetic “locking”; clonal selection and expansion [151, 231] | Resistance mutations in ctDNA; clonal expansion signatures; stable epigenetic/transcriptional resistance programs; persistent imaging evidence of nonresponse; multi-omic confirmation of resistant state [171, 230] | Transition windows narrow; resistance becomes durable; requires switching strategies/targets; supports early interception during plasticity/vulnerability phases to delay or prevent stabilization [13, 151] |
ctDNA: circulating tumor deoxyribonucleic acid; ECM: extracellular matrix; EMT: epithelial-mesenchymal transition; MET: mesenchymal-epithelial transition; scATAC-seq: single-cell assay for transposase-accessible chromatin using sequencing; scRNA-seq: single-cell ribonucleic acid sequencing; UPR: unfolded protein response.
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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