DNA methylation plays an important role in the silence of tissue-specific genes to prevent them from being expressed in the wrong tissue. Aberrant DNA methylation (genome-wide hypomethylation and site-specific hypermethylation) are observed in many types of cancer. DNA methylation patterns are established and maintained through the combined actions of methyltransferase and demethylase, such as DNA methyltransferase (DNMT)-1, DNMT-3, and ten-eleven translocation (TET) family enzymes. It is well known that the process of tumor evolution is complicated with different hallmarks. Early findings put forward the model that focal hypermethylation of tumor suppressor genes (TSG) could straightly trigger transcriptional silencing and malignant transformation, whereas varying levels of DNA methylation also occur at other sites and can differently regulate gene expression and biological processes. The interplay of tumor and immune cells in the tumor microenvironment is complex. Understanding the role of DNA methylation in cancer immunity is critical to better navigate epigenetic agents. Furthermore, a greater understanding of the interaction of DNA methylation with tumor metabolic reprogramming would create a bright avenue for pharmacologic managements of malignancies. In this review, we will describe the molecular mechanisms of DNA methylation abnormalities in cancer biology, introduce the roles of DNA methylation patterns on cancer-immunity cycle and metabolic reprogramming, summarize modulators that are used in targeting DNA remodeling, and highlight the importance of combining epigenome-targeting drugs with other cancer therapies.