The tumor microenvironment (TME) is a dynamic and complex system comprising immune cells, stromal cells, blood vessels, and the extracellular matrix. The cellular and molecular elements can be different among cancer types, but they appear to be crucial for tumor initiation, survival, invasion, and metastasis. During early tumor development, cancer cells create a bidirectional relationship with TME components that allows them to evade immune detection, resist apoptotic processes, and promote angiogenesis and metastasis. Traditionally, cancer progression has been attributed simply to the sequential accumulation of genetic mutations. However, evidence is growing that epigenetic alterations, such as DNA methylation and hydroxymethylation, histone modifications, and microRNA dysregulation, are also important contributors to tumorigenesis. These epigenetic alterations also regulate critical signaling pathways related to apoptosis, autophagy, and cellular differentiation, which have implications for the emergence of aggressive cancer stem-like cells and further metastasis. The recognition of epigenetic regulatory mechanisms has also led to new therapeutic options. Epigenetic drugs, including DNA methyltransferase and histone deacetylase inhibitors, have been shown to reverse the expression of tumor suppressor genes, enhance the efficacy of conventional therapies, block the development of cancer progenitor cells, and reduce recurrence rates. Recognizing epigenetic dysregulation as a hallmark of cancer represents an opportunity to create new biomarkers and targeted treatments. Despite significant advances in surgery, chemotherapy, and radiotherapy, most standard treatments lack precision and typically have significant side effects. The movement toward immunotherapy, targeted therapy, and personalized medicine has allowed for more precise, less invasive, and more tolerable treatment regimens. At the same time, there has been an increasing recognition of the role of mitochondrial dynamics (such as fission, fusion, and mitophagy) as important regulators of tumor metabolism, drug resistance, and apoptosis. Although their clinical significance is still being fully explored, mitochondrial biomarkers and mitochondrial-targeted therapies present diagnostic and therapeutic value. Collectively, the degree to which the TME is responsive to different treatment modalities, the contribution of epigenetics, and the coordinated regulation of mitochondrial dynamics may contribute to a more informed theranostic application toward improving cancer diagnosis, treatment, and patient survival.