Epigenetic Modifiers: Anti-Neoplastic Drugs With Immunomodulating Potential

Front Immunol. 2021 Mar 30:12:652160. doi: 10.3389/fimmu.2021.652160. eCollection 2021.


Cancer cells are under the surveillance of the host immune system. Nevertheless, a number of immunosuppressive mechanisms allow tumors to escape protective responses and impose immune tolerance. Epigenetic alterations are central to cancer cell biology and cancer immune evasion. Accordingly, epigenetic modulating agents (EMAs) are being exploited as anti-neoplastic and immunomodulatory agents to restore immunological fitness. By simultaneously acting on cancer cells, e.g. by changing expression of tumor antigens, immune checkpoints, chemokines or innate defense pathways, and on immune cells, e.g. by remodeling the tumor stroma or enhancing effector cell functionality, EMAs can indeed overcome peripheral tolerance to transformed cells. Therefore, combinations of EMAs with chemo- or immunotherapy have become interesting strategies to fight cancer. Here we review several examples of epigenetic changes critical for immune cell functions and tumor-immune evasion and of the use of EMAs in promoting anti-tumor immunity. Finally, we provide our perspective on how EMAs could represent a game changer for combinatorial therapies and the clinical management of cancer.

Keywords: cancer; epigenetics; immune evasion; immunotherapy; tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Combined Modality Therapy / methods
  • DNA Methylation / drug effects
  • DNA Methylation / immunology
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Epigenesis, Genetic / drug effects*
  • Epigenesis, Genetic / immunology
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Gene Expression Regulation, Neoplastic / immunology
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune Checkpoint Inhibitors / therapeutic use
  • Immunotherapy, Adoptive / methods
  • Neoplasms / genetics
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Protein Processing, Post-Translational / drug effects
  • Protein Processing, Post-Translational / immunology
  • Receptors, Chimeric Antigen / immunology
  • Treatment Outcome
  • Tumor Escape / drug effects*
  • Tumor Escape / genetics
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology


  • Enzyme Inhibitors
  • Immune Checkpoint Inhibitors
  • Receptors, Chimeric Antigen