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mRNA-based cancer therapeutics

Nature Reviews Cancer volume 23, pages 526–543 (2023)Cite this article

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Abstract

Due to the fact that mRNA technology allows the production of diverse vaccines and treatments in a shorter time frame and with reduced expense compared to conventional approaches, there has been a surge in the use of mRNA-based therapeutics in recent years. With the aim of encoding tumour antigens for cancer vaccines, cytokines for immunotherapy, tumour suppressors to inhibit tumour development, chimeric antigen receptors for engineered T cell therapy or genome-editing proteins for gene therapy, many of these therapeutics have shown promising efficacy in preclinical studies, and some have even entered clinical trials. Given the evidence supporting the effectiveness and safety of clinically approved mRNA vaccines, coupled with growing interest in mRNA-based therapeutics, mRNA technology is poised to become one of the major pillars in cancer drug development. In this Review, we present in vitro transcribed mRNA-based therapeutics for cancer treatment, including the characteristics of the various types of synthetic mRNA, the packaging systems for efficient mRNA delivery, preclinical and clinical studies, current challenges and future prospects in the field. We anticipate the translation of promising mRNA-based treatments into clinical applications, to ultimately benefit patients.

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Fig. 1: In vitro transcribed mRNA for cancer therapeutics.
Fig. 2: The development of mRNA cancer vaccine encoding tumour-associated antigens or neoantigens.
Fig. 3: mRNA encoding cytokines and tumour suppressors for cancer therapy.
Fig. 4: mRNA encoding Cas9 mediated genome editing for cancer immunotherapy.
Fig. 5: In vitro and in vivo delivery of mRNA encoding CAR and TCR for T cell engineering.

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Acknowledgements

This work is supported by Basic Science Research Programs from the National Research Foundation of Korea (no. 2022R1C1C2007637 to S.K.), National Natural Science Foundation of China (no. 82122076 to N.K.), Harvard Medical School/Brigham and Women’s Hospital Department of Anaesthesiology Basic Scientist Grant (no. 2420 BPA075 to W.T.), Nanotechnology Foundation (no. 2022A002721 to W.T.), Gillian Reny Stepping Strong Center for Trauma Innovation Breakthrough Innovator Award (no. 113548 to W.T.), Center for Nanomedicine Research Fund (no. 2019A014810 to W.T.), and Farokhzad Family Distinguished Chair Foundation (no. 018129 to W.T.). W.T. is also a recipient of the Khoury Innovation Award (no. 2020A003219) and the American Heart Association (AHA) Collaborative Science Award (no. 2018A004190).

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Author notes

  1. These authors contributed equally: Chuang Liu, Qiangqiang Shi.

Authors and Affiliations

  1. Center for Nanomedicine and Department of Anaesthesiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Chuang Liu, Qiangqiang Shi, Xiangang Huang, Seyoung Koo, Na Kong & Wei Tao

  2. Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China

    Qiangqiang Shi & Na Kong

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  1. Chuang Liu
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All authors researched data for the article, contributed substantially to discussion of the content, wrote, reviewed and edited the manuscript.

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Glossary

5′ and 3′ untranslated regions

(UTRs). Non-coding regulatory regions of mRNA that contain multiple regulatory elements.

5′ Cap

A specially altered nucleotide on the 5′ end of mRNA, which has a substantial role in the initiation of mRNA translation.

Chimeric antigen receptors

(CARs). Receptor proteins that combine antigen binding and T cell activation functions to drive T cells to target specific antigens.

Cytokines

A class of small proteins that modulate autocrine, paracrine and endocrine signalling.

Electroporation

A biological technique in which exogenous substances, such as drugs, DNA or mRNA, are transferred into a cell by applying an electrical field to the cell to increase the permeability of the cell membrane.

High-performance liquid chromatography

(HPLC). An analytical chemistry technique that relies on differences in the chemical interaction of each component of a sample with the sorbent material for the separation, identification and quantification of each component in a mixture.

Immune tolerant

Describes the inability of antigen-specific immune cells to be activated in response to antigen stimulation and to execute a normal immune response.

Ionizable phospholipid

(iPho). A lipid with an ionizable amino group, a phosphate head group and hydrophobic lipid tail; iPhos are positively charged at acidic pH to condense RNA into lipid nanoparticles, but are neutral at physiological pH to minimize toxicity.

Major histocompatibility complex

(MHC). A set of eukaryotic cell surface proteins that can be divided into MHC class I and II molecules.

Open reading frame

(ORF). The most crucial part of mRNA, which contains the coding sequence of the translated protein.

Peripheral blood mononuclear cells

(PBMCs). Blood cells with round nuclei that are generally comprised of lymphocytes (T cells, B cells, natural killer cells), monocytes and a small number of dendritic cells.

Poly(A) tail

A string of adenosine modifications to the 3′ end of mRNA, which plays a crucial part in preventing mRNA degradation and enhancing translation efficiency.

Regulatory T cells

(Treg cells). A subpopulation of T cells that regulate the immune system, maintain tolerance to self antigens and prevent autoimmune diseases.

RNA-dependent RNA polymerase

(RDRP). An enzyme that catalyses the replication of RNA from an RNA template.

Tumour microenvironment

(TME). The non-cancerous environment that surrounds tumour cells, including blood vessels, immune cells, fibroblasts, signalling molecules and extracellular matrix.

Tumour suppressors

Proteins that regulate cells during cell division and replication to prevent cancer.

Type I interferon

(IFN). A cytokine that fulfils an important role in inflammation, immunoregulation, tumour cell recognition and T cell responses.

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Liu, C., Shi, Q., Huang, X. et al. mRNA-based cancer therapeutics. Nat Rev Cancer 23, 526–543 (2023). https://doi.org/10.1038/s41568-023-00586-2

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