RNA in Cancer Immunotherapy: Unlocking the Potential of the Immune System

Abstract

Recent advances in the manufacturing, modification, purification, and cellular delivery of ribonucleic acid (RNA) have enabled the development of RNA-based therapeutics for a broad array of applications. The approval of two SARS-CoV-2-targeting mRNA-based vaccines has highlighted the advances of this technology. Offering rapid and straightforward manufacturing, clinical safety, and versatility, this paves the way for RNA therapeutics to expand into cancer immunotherapy. Together with ongoing trials on RNA cancer vaccination and cellular therapy, RNA therapeutics could be introduced into clinical practice, possibly stewarding future personalized approaches. In the present review, we discuss recent advances in RNA-based immuno-oncology together with an update on ongoing clinical applications and their current challenges.

Figure 1.

Overview of coding and noncoding RNA structures. Left, in vitro transcription (iVT) of messenger RNA (mRNA). mRNA has several conserved features, including a 5′ cap structure, two extended untranslated regions (UTR) at the 5′ and 3′ end of the ORF, and a 3′ poly-A tail. The final iVT product can be mRNA or self-amplifying mRNA. Right, solid-phase synthesis of noncoding and antisense oligonucleotides. Abbreviations: ASO, antisense oligonucleotides; mRNA, messenger RNA; UTR, untranslated region; rNTP, ribonucleoside triphosphates; miRNA, microRNA; siRNA, small interfering RNA. Adapted from an image created with BioRender.com.

Figure 2.

Overview of active mRNA-based immunotherapeutic strategies. Left, LNP-antigen mRNA vaccine delivered systemic or locally, followed by antigen expression resulting in T-cell priming and eventually cancer cell killing. Right, monocytes or hematopoietic progenitor cells are isolated from blood, further cultured, and differentiated into DCs. mRNA is then used to load the DCs ex vivo with tumor antigens. The modified DCs are administered to patients, where they will prime T cells, eventually resulting in the killing of cancer cells. Adapted from an image created with BioRender.com.

Figure 3.

Overview of passive immunotherapeutic strategies. Left, systemic administration of TCR and CAR LNP-mRNA causes specific uptake by CD8⁺ T cells, followed by expression and antigen recognition, resulting in cancer cell death. Top right, ex vivo TCR/CAR LNP-mRNA manipulation of T cells, followed by systemic administration. Bottom right, intratumoral or systemic delivery of LNP-mRNA encoding monoclonal antibodies (mAbs), immune-inducing cytokines, or stimulatory receptors. Abbreviations: TCR, T-cell receptor; CAR, chimeric antigen receptor. Adapted from an image created with BioRender.com.