Interweaving Tumor Heterogeneity into the Cancer Epigenetic/Metabolic Axis

Significance: The epigenomic/metabolic landscape in cancer has been studied extensively in the past decade and forms the basis of various drug targets. Yet, cancer treatment remains a challenge, with clinical trials exhibiting limited efficacy and high relapse rates. Patients respond differently to therapy, which is fundamentally attributed to tumor heterogeneity, both across and within tumors. This review focuses on the interactions between the heterogeneous tumor microenvironment (TME) and the epigenomic/metabolic axis in cancer, as well as the emerging technologies under development to aid heterogeneity studies. Recent Advances: Interlinks between epigenetics and metabolism in cancer have been reported. Emerging studies have unveiled interactions between the TME and cancer cells that play a critical role in regulating epigenetics and reprogramming cancer metabolism, suggesting a three-way cross talk. Critical Issues: This cross talk accentuates the multiplex nature of cancer, and the importance of considering tumor heterogeneity in various epigenomic/metabolic cancer studies. Future Directions: With the advancement in single-cell profiling, it may be possible to identify cancer subclones and their unique vulnerabilities to develop a multimodal therapy. Drugs targeting the TME are currently being studied, and a better understanding of the TME in regulating cancer epigenetics and metabolism may hold the key to identifying novel therapeutic targets.