Drug-Tolerant Cancer Cell States: Epigenetic Plasticity, Chromatin Rewiring and Therapeutic Vulnerabilities

A major obstacle to durable cancer treatment is the ability of tumor cells to survive therapeutic pressure without acquiring genetic mutations. Rather than relying solely on the selection of pre-existing resistant clones, cancer cells can enter reversible, slow-cycling “drug-tolerant persister” states that allow them to weather chemotherapy, targeted agents, and endocrine therapy. These states are increasingly recognized as a reservoir from which relapse and stable resistance emerge.Epigenetic plasticity sits at the center of this adaptation. Through chromatin remodeling, altered histone modifications, DNA methylation changes, and rewired transcriptional programs, cancer cells shift their identity and stress-response repertoire in a non-genetic and often reversible manner. Because these mechanisms are dynamic and enzymatically driven, they also create dependencies—actionable vulnerabilities that can be exploited to prevent tolerance, resensitize tumors, or eliminate persister populations before stable resistance takes hold.This Research Topic keeps chromatin regulation and epigenetic mechanisms at its core while placing them in the broader and highly relevant context of therapy resistance, drug-tolerant persister states, and non-genetic adaptation to treatment. We aim to bring together mechanistic and translational studies exploring how cancer cells exploit epigenetic plasticity, chromatin remodeling, and adaptive transcriptional programs to survive therapeutic pressure across tumor types, and how these mechanisms can be translated into actionable therapeutic strategies.We welcome Original Research, Reviews, Mini Reviews, Methods, and Perspectives spanning basic mechanism to clinical translation, addressing themes including (but not limited to):o Drug-tolerant persister cells: origins, dynamics, reversibility, and eradication strategieso Chromatin regulators and epigenetic complexes (writers, readers, erasers, ATP-dependent remodelers) in treatment survivalo Histone modifications, DNA methylation, and higher-order chromatin architecture during adaptationo Adaptive and rewired transcriptional programs underlying non-genetic resistanceo Endocrine- and targeted-therapy resistance driven by epigenetic mechanismso Interplay between the DNA damage response, oncogenic signaling, and chromatin stateo CRISPR and RNAi functional screens identifying epigenetic dependencieso Single-cell and multi-omics approaches to resolve heterogeneous tolerant stateso Rational drug combinations targeting epigenetic plasticity to prevent or reverse toleranceo Translational validation in organoids, PDX models, and clinical cohortso AI- and ML-based approaches for drug repositioning, biomarker discovery, or rational combination designPlease note that manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases that are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are out of the scope of this Research Topic. Topic editors: Annamaria Salvati, Alka Singh, Giovanni Nassa Source: https://www.frontiersin.org/research-topics/83610/drug-tolerant-cancer-cell-states-epigenetic-plasticity-chromatin-rewiring-and-therapeutic-vulnerabilities