Emerging Role of Circular RNAs in Hepatocellular Carcinoma Immunotherapy

Abstract

Hepatocellular carcinoma (HCC) is a highly fatal malignancy with limited therapeutic options and high recurrence rates. Recently, immunotherapeutic agents such as immune checkpoint inhibitors (ICIs) have emerged as a new paradigm shift in oncology. ICIs, such as programmed cell death protein 1 (PD-1) inhibitors, have provided a new source of hope for patients with advanced HCC. Yet, the eligibility criteria of HCC patients for ICIs are still a missing piece in the puzzle. Circular RNAs (circRNAs) have recently emerged as a new class of non-coding RNAs that play a fundamental role in cancer pathogenesis. Structurally, circRNAs are resistant to exonucleolytic degradation and have a longer half-life than their linear counterparts. Functionally, circRNAs possess the capability to influence various facets of the tumor microenvironment, especially at the HCC tumor-immune synapse. Notably, circRNAs have been observed to control the expression of immune checkpoint molecules within tumor cells, potentially impeding the therapeutic effectiveness of ICIs. Therefore, this renders them potential cancer-immune biomarkers for diagnosis, prognosis, and therapeutic regimen determinants. In this review, the authors shed light on the structure and functional roles of circRNAs and, most importantly, highlight the promising roles of circRNAs in HCC immunomodulation and their potential as promising biomarkers and immunotherapeutic regimen determinants.

Keywords: circular RNAs (circRNAs); cytotoxic T lymphocytes; hepatocellular carcinoma (HCC); immunotherapy; natural killer cells; tumor microenvironment (TME).

Figure 1

Circular RNA (circRNA) biogenesis. Schematic presentation of the different mechanisms of circRNAs biogenesis: intron painting (a), RBP pairing (b), Lariat driven (c), and the self-circularization of introns (d). ciRNA, intronic circRNA; EcircRNA, exonic circRNA; EIcircRNAs, exon-intron circRNA; RBP, RNA-binding protein; ss, splice site.

Figure 2

Different functional roles of circular RNAs (circRNAs). Schematic representation of different mechanisms of action of circRNAs represented as (1) microRNA (miRNA) sponge, (2) protein sponge or decoy (3) protein scaffolding, (4) transcriptional regulation, (5) translation to proteins, and peptide (6) regulation of epigenetic alterations.

Figure 3

A snapshot of potential circRNAs as promising modulators of tumor microenvironment in HCC. Ab, antibody; ADO, adenosine; AKT, AKT serine/threonine kinase 1; AMP, adenosine monophosphate; CD39, ectonucleoside triphosphate diphosphohydrolase 1; CD73, 5′-nucleotidase ecto; CD8, cluster of differentiation 8; CXCL10, C-X-C motif chemokine ligand 10; CXCR3, C-X-C motif chemokine receptor 3; DPP4, dipeptidyl peptidase 4; eATP, extracellular adenosine triphosphate; EIF4A3, eukaryotic translation initiation factor 4A3; HCC, hepatocellular cancer; HIF-1a, hypoxia inducible factor 1 subunit alpha; M⁶A, N6-methyladenosine; MHC, major histocompatibility complex; NK, natural killer; NKG2D, killer cell lectin-like receptor K1; PD-1, programmed cell death protein 1; PD-L1, CD27/programmed cell death protein 1 ligand; PI3K, phosphoinositide 3-kinase; PIK3R1, phosphoinositide-3-kinase regulatory subunit 1; RHBDD1, rhomboid domain containing 1; Snail, snail family transcriptional repressor 1; TIM-3, hepatitis A virus cellular receptor 2; ULBP1, UL16 binding protein 1; YTHDF1, YTH N6-methyladenosine RNA binding protein F1.