Mechanistic sequence linking therapeutic triggers to adaptive phenotypes and candidate vulnerabilities.
| Upstream trigger | Adaptive signaling cascade | Cellular phenotype | Candidate dependency or vulnerability |
|---|---|---|---|
| Oxidative stress | NRF2-linked antioxidant defense, glutathione metabolism, mitochondrial redox control | Redox-adapted persister survival | Dependence on antioxidant buffering or redox homeostasis |
| DNA damage or replication stress | DNA damage response, checkpoint signaling, repair-pathway activation | Repair-dependent survival state | Dependence on DNA repair or checkpoint pathways |
| Proteotoxic stress | Unfolded protein response, PERK-eIF2α, ATF4, IRE1-XBP1 signaling | Proteostasis-dependent tolerance | Dependence on ER stress adaptation or protein-quality control |
| Metabolic disruption | AMPK activation, mTOR suppression, autophagy, mitochondrial compensation | Metabolically constrained persister state | Dependence on nutrient utilization, autophagy, or mitochondrial function |
| Oncogenic pathway inhibition | RTK rewiring, MAPK/PI3K-AKT bypass signaling | Adaptive signaling tolerance | Dependence on bypass signaling circuits |
| Hypoxia or stromal remodeling | HIF signaling, inflammatory cytokines, ECM and stromal growth-factor signaling | Microenvironment-supported plasticity | Dependence on hypoxia adaptation or tumor-stroma signaling |
| Epigenetic remodeling | Chromatin remodeling, enhancer rewiring, DNA methylation shifts | Reversible transcriptional state transition | Dependence on epigenetic regulators or state-maintaining transcriptional circuits |
AMPK: AMP-activated protein kinase; ATF4: activating transcription factor 4; ECM: extracellular matrix; eIF2α: eukaryotic translation initiation factor 2 alpha; NRF2: nuclear factor erythroid 2-related factor 2; HIF: hypoxia-inducible factor; IRE1: inositol-requiring enzyme 1; MAPK: mitogen-activated protein kinase; PERK: protein kinase R-like endoplasmic reticulum kinase; PI3K-AKT: phosphoinositide 3-kinase-protein kinase B; RTK: receptor tyrosine kinase; XBP1: X-box binding protein 1.
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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