Emerging biomarkers for monitoring tumor state transitions during therapy.
| Biomarker category | Technology/platform | Biological information captured | Clinical applications | Limitations |
|---|---|---|---|---|
| Single-cell transcriptomics | scRNA-seq, high-throughput droplet-based sequencing platforms | Gene expression states of individual tumor cells; identification of rare adaptive populations such as drug-tolerant persister cells; mapping of cellular state transitions [185, 186] | Identification of therapy-resistant subpopulations; characterization of tumor heterogeneity; monitoring transcriptional state transitions during treatment | Requires tumor tissue sampling; high cost; complex computational analysis |
| Single-cell epigenomics | scATAC-seq, chromatin accessibility profiling, multi-omics single-cell platforms | Epigenetic regulatory states, enhancer activity, and transcription factor networks governing tumor cell identity [187, 188] | Identification of epigenetic programs driving plasticity and therapy resistance; detection of lineage state transitions | Technical complexity; limited clinical implementation; dependence on high-quality tissue samples |
| ctDNA | Liquid biopsy assays, digital polymerase chain reaction (PCR), next-generation sequencing of plasma DNA | Detection of tumor-derived mutations and clonal evolution in circulation; dynamic monitoring of tumor genomic alterations during therapy [171, 177] | Longitudinal monitoring of treatment response; early detection of emerging resistance mutations; minimal residual disease assessment | Limited ability to capture transcriptional or phenotypic states; sensitivity may vary with tumor burden |
| CTCs | Microfluidic capture platforms, immunomagnetic enrichment, single-cell analysis of CTCs | Phenotypic and molecular characterization of viable tumor cells undergoing dissemination and therapeutic adaptation [189, 190] | Monitoring tumor evolution and metastatic potential; assessment of therapy-induced phenotypic transitions | Low abundance in circulation; technical challenges in isolation and characterization |
| Epigenetic biomarkers | DNA methylation profiling, chromatin accessibility assays, enhancer landscape analysis | Epigenetic states associated with tumor plasticity, lineage transitions, and drug tolerance [187, 191] | Identification of regulatory state changes associated with therapy resistance; potential biomarkers for adaptive tumor states | Epigenetic states may be heterogeneous across tumor regions; clinical standardization still developing |
| Metabolic biomarkers | Metabolomics profiling, metabolic imaging, measurement of metabolic pathway activity | Metabolic adaptations occurring during therapeutic stress, including altered nutrient dependencies and mitochondrial function [90, 97] | Identification of therapy-induced metabolic vulnerabilities; monitoring tumor metabolic reprogramming during treatment | Metabolic signals can be influenced by systemic physiological factors; interpretation may be complex |
| Imaging biomarkers | fMRI, PET imaging, hypoxia imaging, metabolic imaging tracers | Spatial and temporal changes in tumor metabolism, perfusion, hypoxia, and treatment response [187, 192] | Non-invasive monitoring of tumor physiology during therapy; detection of dynamic treatment responses | Limited molecular resolution; may not capture cellular-level state transitions |
CTCs: circulating tumor cells; ctDNA: circulating tumor deoxyribonucleic acid; fMRI: functional magnetic resonance imaging; PET: positron emission tomography; scATAC-seq: single-cell assay for transposase-accessible chromatin using sequencing; scRNA-seq: single-cell ribonucleic acid sequencing.
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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This research received no external funding.
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