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  • Review Article
  • Published:

Getting the right combination to break the epigenetic code

Nature Reviews Clinical Oncology volume 22, pages 117–133 (2025)Cite this article

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Abstract

Rapid advances in the field of epigenetics have facilitated the development of novel therapeutics targeting epigenetic mechanisms that are hijacked by cancer cells to support tumour growth and progression. Several epigenetic agents have been approved by the FDA for the treatment of cancer; however, the efficacy of these drugs is dependent on the underlying biology and drivers of the disease, with inherent differences between solid tumours and haematological malignancies. The efficacy of epigenetic drugs as single agents remains limited across most cancer types, which has spurred the clinical development of combination therapies, with the hope of attaining synergistic activity and/or overcoming treatment resistance. In this Review we discuss clinical advances that have been achieved with the use of epigenetic agents in combination with chemotherapies, immunotherapies or other targeted agents, including epigenetic–epigenetic combinations, as well as limitations and challenges associated with these combinatorial strategies. So far, the success of combination therapies targeting epigenetic mechanisms has generally been confined to haematological malignancies, with limited efficacy observed in patients with solid tumours. Nevertheless, this Review captures the field of epigenetic combination therapies across the spectra of haematology and oncology, highlighting opportunities for precision therapy to effectively harness the potential of epigenetic agents and produce meaningful improvements in clinical outcomes.

Key points

  • The activity of epigenetic drugs is dependent on underlying tumour biology, with distinct differences across solid tumours and haematological malignancies.

  • Current epigenetic drugs have meaningful clinical efficacy as single agents in certain haematological malignancies, particularly acute myeloid leukaemia, peripheral T cell lymphoma or cutaneous T cell lymphoma, but generally limited efficacy in solid tumour settings.

  • Epigenetic agents have been combined with chemotherapies, immunotherapies and targeted therapies, including other epigenetic drugs, in an effort to target parallel pathways of tumorigenesis, enhance cancer cell death and overcome mechanisms of resistance.

  • Epigenetic combination therapies have had limited success in solid tumours, the reasons for which are poorly defined, but this pattern might signal that solid tumours have greater complexity and are not highly dependent on altered epigenetic pathways.

  • Haematological malignancies including peripheral T cell lymphoma, particularly subtypes with a T follicular helper phenotype, and acute myeloid leukaemia also seem to be uniquely sensitive to epigenetic combination therapies, underscoring that successful outcomes are possible if cancers that are highly dependent on aberrant epigenetic pathways can be identified and selectively targeted.

  • Altogether, the experience with epigenetic combination therapies so far highlights the importance of precision medicine and pinpointing specific epigenetic drivers of disease to translate promising preclinical results into clinically meaningful change for patients.

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Fig. 1: Epigenetic therapies and their mechanism of action.
Fig. 2: Selected mechanisms of synergy between epigenetic drugs and chemotherapies, immunotherapies and targeted therapies.

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Authors and Affiliations

  1. Division of Hematology and Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA

    Seda S. Tolu, Aaron D. Viny, Jennifer E. Amengual, Barbara Pro & Susan E. Bates

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  1. Seda S. Tolu
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  2. Aaron D. Viny
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  3. Jennifer E. Amengual
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  4. Barbara Pro
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  5. Susan E. Bates
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The authors contributed equally to all aspects of the article.

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Correspondence to Seda S. Tolu.

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Competing interests

A.D.V. has served on advisory boards for Arima Genomics. J.E.A. has served on advisory boards for ADC Therapeutics. B.P. has received research grants from Ono Pharmaceuticals and SciTech. S.E.B. has served on data safety monitoring boards for Acrivon, Amgen, Elmedix, Merck, Pegascy, Pfizer and RenovoRx. S.S.T. declares no competing interests.

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Tolu, S.S., Viny, A.D., Amengual, J.E. et al. Getting the right combination to break the epigenetic code. Nat Rev Clin Oncol 22, 117–133 (2025). https://doi.org/10.1038/s41571-024-00972-1

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