Epigenetic heterogeneity and plasticity in therapy‐induced tumor states through single‐cell multi‐omics

Therapeutic resistance and disease recurrence remain major unresolved challenges in oncology, primarily driven by tumor heterogeneity and the inherent plasticity of cancer cells. Although multiple biological mechanisms contribute to these processes, epigenetic mechanisms are the key regulators of clonal diversification and adaptive transcriptional reprogramming under treatment pressure. This regulatory layer operates through reversible transcriptional changes that are independent of DNA sequence alterations, enabling cancer cells to respond to a selective environment. Recent advances in analytical methodologies, particularly single-cell multi-omics approaches, have markedly improved our capacity to dissect these regulatory processes at a single-cell resolution. This review explores how diverse therapeutics, including chemotherapy, targeted agents, immunotherapy, hormonal interventions, and epigenetic drugs, induce the widespread remodeling of DNA methylation patterns, histone modifications, and chromatin accessibility. These therapy-induced molecular changes drive transitions to distinct cellular states that confer survival advantages such as drug-tolerant persister (DTP) phenotypes, senescence-like populations, epithelial-mesenchymal transition (EMT) states, and immune-evasive cell populations. We further evaluated the current single-cell multi-omics platforms for profiling chromatin-based plasticity and identifying biomarkers with direct clinical relevance. Finally, we discuss how integrative multi-layer analyses enable comprehensive characterization of tumor-state evolution, providing a conceptual framework for precision oncology strategies aimed at overcoming resistance.