Roles and therapeutic implications of m6A modification in cancer immunotherapy

Abstract

Recent studies have demonstrated that N6-methyladenosine (m6A), the most abundant, dynamic, and reversible epigenetic RNA modification in eukaryotes, is regulated by a series of enzymes, including methyltransferases (writers), demethylases (erasers), and m6A recognition proteins (readers). Aberrant regulation of m6A modification is pivotal for tumorigenesis, progression, invasion, metastasis, and apoptosis of malignant tumors. Immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, as recognized by the 2018 Nobel Prize in Medicine and Physiology. However, not all cancer patients response to ICI therapy, which is thought to be the result of intricate immune escape mechanisms. Recently, numerous studies have suggested a novel role for m6A epigenetic modification in the regulation of tumor immune evasion. Herein, we review the relevant mechanisms of m6A regulators in regulating various key signaling pathways in cancer biology and how m6A epigenetic modifications regulate the expression of immune checkpoints, opening a new window to understand the roles and mechanisms of m6A epigenetic modifications in regulating tumor immune evasion. In addition, we highlight the prospects and development directions of future combined immunotherapy strategies based on m6A modification targeting, providing directions for promoting the treatment outcomes of immune checkpoint inhibitors.

Keywords: cancer; immune checkpoints; immunotherapy; m6A modification; m6A-regulator inhibitors.

Figure 1

The dynamic and reversible m6A RNA modification is regulated by “writers”, “erasers.”, and “readers”. M6 A methylation is installed by the methyltransferase complex comprising the core catalytic subunit METTL3/METTL14/WTAP and other regulatory proteins. The erasers are composed of FTO, ALKBH5, and ALKBH3, removing the methyl group by demethylation. The function of m6A is mediated by m6A ‘reader’, recognizing m6A marks to activate downstream regulatory pathways, which mediate various functions of RNA, such as RNA splicing, export, decay, stabilization and translation. And the reader proteins mainly include YTHDF1/2/3, YTHDC1/2, the IGF2BP family, HNRNPs (HNRNPA2B1, HNRNPC and HNRNPG), eIF3, PRRC2A, and FMR1.

Figure 2

Molecular structures of RNA methylations. The m6Am modification is methylated by “writers”, including METTL3, METTL4 and PCIF1, and eliminated by “eraser” FTO.

Figure 3

List of common immune checkpoints and its related inhibitors in clinical trials PD1, programmed cell death 1; PDL1, programmed cell death 1 ligand 1; CTLA4, cytotoxic T lymphocyte antigen 4; TIM-3, T cell immunoglobulin mucin receptor 3;CD40L, CD40 ligand; ICOS, inducible T cell co-stimulator; ICOSL, inducible T cell co-stimulator ligand; LAG3, lymphocyte activation gene 3 protein; MHC, major histocompatibility complex; OX40L, OX40 ligand; TIGIT, T cell immunoreceptor with Ig and ITIM domains.

Figure 4

Overview of multiple functions of m6A regulators in various cancers mediated by some signaling pathways. The core pathways regulate many biological functions of tumors, including tumor occurrence, migration, proliferation, apoptosis, differentiation metastasis, multidrug resistance, treatment response and cancer development. The MYC pathway, Wnt/β-Catenin pathway, PI3K/AKT/mTOR pathway, p53 pathway, EMT pathway, and other pathways are included in the key cancer pathways.