Single-cell epigenomics of colorectal cancer

Abstract

Colorectal cancer (CRC) exhibits remarkable phenotypic heterogeneity that cannot be fully explained by genetic alterations alone. Advances in single-nucleus assay for transposase-accessible chromatin sequencing have revealed chromatin accessibility as a central regulatory layer shaping tumor identity, cellular plasticity and therapeutic response. In this Review, we synthesize recent single-cell epigenomic studies to outline an emerging regulatory principle for CRC. From an epigenetic perspective, CRC can be conceptualized as two distinct epigenomic states, intrinsic consensus molecular subtype (iCMS)2 and iCMS3, defined by divergent cis-regulatory element activities across distal enhancer and promoter landscapes. Tumor progression is accompanied by stepwise regulatory rewiring, encompassing erosion of differentiation programs in adenomas, regulatory bifurcation during malignant transformation, oncofetal reprogramming associated with therapy resistance and organotropic adaptation during metastasis. We further discuss how stromal and immune compartments undergo dynamic epigenomic remodeling, converging toward a concept of iCMS-defined epigenomic ecosystems, and how genomic alterations engage in bidirectional crosstalk with chromatin states to generate intratumoral heterogeneity. Finally, we highlight translational applications including epigenetic–immune combination therapies, liquid biopsy-based monitoring, spatial epigenomics and artificial intelligence-driven modeling. Colorectal cancer (CRC) is a leading cause of cancer-related deaths, characterized by genetic mutations and phenotypic plasticity. Recent studies have highlighted the role of nongenetic mechanisms, particularly epigenomic plasticity, in CRC progression. Here we explore how single-cell chromatin accessibility profiling has advanced our understanding of CRC by revealing distinct regulatory states and dynamic chromatin remodeling. The authors synthesized recent findings from single-cell epigenomics, highlighting iCMS2 and iCMS3 as two main epigenomic states with distinct cis-regulatory landscapes. They further integrated transcription factor-regulated phenotypic plasticity and oncofetal reprogramming in CRC, both contributing to therapeutic resistance. These findings suggest that chromatin accessibility patterns can predict tumor lineage and therapeutic vulnerabilities. This review proposes that targeting epigenomic states could enhance precision oncology, with future research focusing on integrating spatial epigenomics and artificial intelligence-driven models to further elucidate CRC’s regulatory architecture. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.