Treatment History and the Accessibility of Future Tumor States: From Current Response to History-Dependent Adaptation

Cancer treatment is commonly evaluated through measurable changes in the present tumor state. However, therapy can also modify how a tumor and its surrounding biological system respond to subsequent challenges. Drug-tolerant persister states, phenotypic plasticity, treatment-induced remodeling of the tumor microenvironment, and acquired resistance suggest that interaction history may remain functionally relevant even after an acute treatment response has subsided. We propose considering this history-dependent future response potential in terms of changes in the probability, timing, persistence, and resource requirements of subsequent state transitions. Importantly, consequences of prior treatment may be distributed beyond residual malignant cells across stromal, immune, extracellular, and systemic compartments. Longitudinal single-cell profiling, lineage tracing, patient-derived organoids, and tumor explants increasingly make these differences experimentally accessible. This perspective does not replace established mechanisms of resistance; it provides a relational framework for asking how previous treatment changes what the tumor–host system can make possible next. Preprint v1.0. This manuscript has not undergone peer review.