Simple SummaryEpithelial-to-mesenchymal transition (EMT) is a complex program by which epithelial cells lose epithelial characteristics whilst acquiring mesenchymal features. EMT was coined in the 1980s and initially thought to involve a binary switch between epithelial and mesenchymal states. However, mounting work suggests that EMT involves intermediate states or hybrid epithelial/mesenchymal (E/M) phenotypes. In the context of many cancers, such as breast cancers, these hybrid states retain characteristics of both epithelial and mesenchymal cells, and have been linked to poor survival, metastasis, and resistance to treatment. In this Review, the authors examine the complex layers of molecular interactions governing EMT in cancer. The underlying drivers of these states, namely EMT-transcription factors, epigenetic regulators, and non-coding RNAs, as well as the influence of EMT on the immune response, are discussed, and in doing so, this Review outlines valuable mechanistic insights for the reversion of EMT and potential avenues for therapeutic intervention.AbstractCellular plasticity in cancer enables adaptation to selective pressures and stress imposed by the tumor microenvironment. This plasticity facilitates the remodeling of cancer cell phenotype and function (such as tumor stemness, metastasis, chemo/radio resistance), and the reprogramming of the surrounding tumor microenvironment to enable immune evasion. Epithelial plasticity is one form of cellular plasticity, which is intrinsically linked with epithelial–mesenchymal transition (EMT). Traditionally, EMT has been regarded as a binary state. Yet, increasing evidence suggests that EMT involves a spectrum of quasi-epithelial and quasi-mesenchymal phenotypes governed by complex interactions between cellular metabolism, transcriptome regulation, and epigenetic mechanisms. Herein, we review the complex cross-talk between the different layers of epithelial plasticity in cancer, encompassing the core layer of transcription factors, their interacting epigenetic modifiers and non-coding RNAs, and the manipulation of cancer immunogenicity in transitioning between epithelial and mesenchymal states. In examining these factors, we provide insights into promising therapeutic avenues and potential anti-cancer targets.