Cancer cells undergo metabolic adaptations to sustain their growth and proliferation under several stress conditions thereby displaying metabolic plasticity. Epigenetic modification is known to occur at the
DNA,
histone, and
RNA level, which can alter
chromatin state. For almost a century, our focus in
cancer biology is dominated by oncogenic mutations. Until recently, the connection between metabolism and epigenetics in a reciprocal manner was spotlighted. Explicitly, several metabolites serve as substrates and co-factors of epigenetic
enzymes to carry out post-translational modifications of
DNA and
histone. Genetic mutations in metabolic
enzymes facilitate the production of oncometabolites that ultimately impact epigenetics. Numerous evidences also indicate epigenome is sensitive to
cancer metabolism. Conversely, epigenetic dysfunction is certified to alter metabolic
enzymes leading to
tumorigenesis. Further, the bidirectional relationship between epigenetics and metabolism can impact directly and indirectly on immune microenvironment, which might create a new avenue for drug discovery. Here we summarize the effects of metabolism reprogramming on epigenetic modification, and vice versa; and the latest advances in targeting metabolism-epigenetic crosstalk. We also discuss the principles linking
cancer metabolism, epigenetics and immunity, and seek optimal
immunotherapy-based combinations.