Background

Conventional immune checkpoint blockade (ICB) therapies have significantly improved survival rates in cancer patients, but their efficacy remains limited to a subset of patients. Tumor immune evasion, the ability of cancer cells to evade immune surveillance, is a major mechanism of resistance. Previous studies have primarily focused on genomic DNA mutations or the regulation of cell surface protein interactions. In contrast, the role of RNA epitranscriptomic modifications, which dynamically regulate gene expression at the post-transcriptional level, has been largely unexplored. Recent studies have revealed that these chemical modifications play a crucial role in regulating the stability of immune evasion genes and remodeling the tumor microenvironment (TME). The ability to precisely control protein synthesis at the post-transcriptional level through reversible RNA modifications, without altering the gene sequence itself, has emerged as a promising new target for cancer immunotherapy.

Key Findings

Cancer cells utilize enzymes that induce RNA modifications to disrupt immune surveillance. One of the most prominent modifications is N6-methyladenosine (m6A), where a methyl group is added to the 6th carbon of adenosine. The methyltransferase complex METTL3 and METTL14 play a role in increasing the stability of transcripts of immune checkpoint proteins, such as programmed death-ligand 1 (PD-L1), and immune-suppressive factors by inducing m6A modifications. Consequently, the expression of immune-suppressive ligands on the surface of cancer cells increases, making it easier for T cells to be inhibited. Furthermore, 5-methylcytosine (m5C) modification also contributes to tumor immune evasion. It has been shown that the RNA methyltransferase NSUN2 reduces the translational efficiency of mRNAs encoding immunostimulatory cytokines, thereby inhibiting T cell activation. In addition, the NAT10 enzyme, which induces N4-acetylcytidine (ac4C) modification, promotes the translation of PD-L1 mRNA, further strengthening the defense mechanisms of cancer cells. Conversely, inhibition of RNA modification regulatory enzymes leads to the restoration of interferon-gamma signaling within the tumor tissue and increased infiltration of cytotoxic T cells. In animal studies, tumors treated with methyltransferase inhibitors exhibited significantly reduced tumor size compared to those treated with ICIs alone, demonstrating a synergistic therapeutic effect.

Significance and Future Directions

Therapies that target RNA chemical modifications are considered a potential solution to overcome the low response rates observed with conventional ICIs. This is because they can convert so-called "cold tumors," which are poorly infiltrated by T cells, into "hot tumors," where T cells are actively recruited. Currently, global pharmaceutical companies are actively developing small molecule inhibitors targeting key modification-regulating proteins, such as METTL3 and FTO. Candidate drugs in clinical trials have demonstrated that their anti-cancer efficacy is maximized when used in combination with existing PD-1/PD-L1 inhibitors, rather than as monotherapy. However, RNA epitranscriptomic modifications also play essential roles in the physiological functions of normal cells, so precise targeting is crucial. Uncontrolled inhibition may lead to serious systemic side effects. The development of tumor-specific delivery systems and companion diagnostic tools to pre-determine the RNA modification patterns of patients are necessary for successful clinical application.