Unraveling the epigenetic code in cancer cell–tumor microenvironment crosstalk

Epigenetics plays a central role in cancer development and progression by governing the expression of genes involved in these processes. Accumulating evidence strongly indicates that these mechanisms not only alter cancer cell-intrinsic properties but also mediate reciprocal interactions between cancer cells and the tumor microenvironment (TME). In the context of cancer cell-intrinsic changes, epigenetic alterations contribute to cancer cell plasticity by regulating stemness, cell state transitions, and therapy resistance. In addition, epigenetic changes are a key driver of the establishment of a tumor-supportive environment by modifying the states of TME components, including fibroblasts, macrophages, and myeloid-derived suppressor cells. Epigenetic reprogramming in cancer cells and TME components is often induced by factors such as hypoxia and the secretion of exosomal long noncoding RNAs (lncRNAs), cytokines, and metabolites. In this review, we discuss various epigenetic mechanisms controlling cancer cell-intrinsic states, cancer cell-TME crosstalk, current epigenetic therapies, and future research directions that may lead to the discovery of new biomarkers and the development of effective epigenetic anticancer therapeutics.