The landscape of cancer diagnostics has been fundamentally transformed by the emergence of minimal residual disease (MRD) detection technologies, with epigenetic mechanisms playing a pivotal role in understanding the molecular complexity of cancer.1 Epigenetic modifications, particularly DNA methylation (DNAm) and chromatin accessibility (ChrAcc), have emerged as critical determinants in tracking and comprehending residual cancer cells that persist after primary treatment.2 DNAm represents a sophisticated molecular mechanism through which cancer cells maintain their adaptive state, enabling MRD detection with unprecedented precision.3 Recent single-cell sequencing technologies have revealed that methylation patterns serve as dynamic molecular signatures that can distinguish between active and dormant cancer cell populations.4 These epigenetic modifications act as molecular switches, regulating gene expression and cellular plasticity without altering the underlying genetic code, thus providing a nuanced understanding of cancer cell behavior beyond traditional genetic analysis.5 ChrAcc, another crucial epigenetic dimension, offers complementary insights into MRD detection. By examining the openness of chromatin regions, specific genomic loci that remain accessible in residual cancer cells can be identified, even after extensive treatment.2 This approach allows the identification of rare cancer cell populations that might otherwise escape conventional detection methods (Fig. 1A).