N6-Methyladenosine RNA Modification: An Emerging Immunotherapeutic Approach to Turning Up Cold Tumors

Abstract

Immunotherapy is a novel clinical approach that has shown clinical efficacy in multiple cancers. However, only a fraction of patients respond well to immunotherapy. Immuno-oncological studies have identified the type of tumors that are sensitive to immunotherapy, the so-called hot tumors, while unresponsive tumors, known as “cold tumors,” have the potential to turn into hot ones. Therefore, the mechanisms underlying cold tumor formation must be elucidated, and efforts should be made to turn cold tumors into hot tumors. N6-methyladenosine (m6A) RNA modification affects the maturation and function of immune cells by controlling mRNA immunogenicity and innate immune components in the tumor microenvironment (TME), suggesting its predominant role in the development of tumors and its potential use as a target to improve cancer immunotherapy. In this review, we first describe the TME, cold and hot tumors, and m6A RNA modification. Then, we focus on the role of m6A RNA modification in cold tumor formation and regulation. Finally, we discuss the potential clinical implications and immunotherapeutic approaches of m6A RNA modification in cancer patients. In conclusion, m6A RNA modification is involved in cold tumor formation by regulating immunity, tumor-cell-intrinsic pathways, soluble inhibitory mediators in the TME, increasing metabolic competition, and affecting the tumor mutational burden. Furthermore, m6A RNA modification regulators may potentially be used as diagnostic and prognostic biomarkers for different types of cancer. In addition, targeting m6A RNA modification may sensitize cancers to immunotherapy, making it a promising immunotherapeutic approach for turning cold tumors into hot ones.

Identification of RNA Methylation-Related lncRNAs Signature for Predicting Hot and Cold Tumors and Prognosis in Colon Cancer

“…The expression levels of PD-1, PD-L1, HAVCR2, CTLA4, LDHA, LGALS9, TNFRSF18, YTHDF1, LAG3, CD40, TNFRSF4, TNFRSF9, CD86, B2M, and CD8A were higher in Cluster2, whereas PDCD1LG2, IL12A, PVR, and JAK1 were higher in Cluster 2 ( Figure 5D ). Previous studies have shown that high immune scores and activation of suppressive immune checkpoints (like HAVCR2, PD-L1, CTLA-4) play a crucial role in “hot tumors” ( Zhan et al, 2021 ). “Hot tumors” are more likely to benefit from immune checkpoint blockade (ICB) therapy, whereas “cold tumors” with low levels of immune infiltration are more likely to become resistant to immunotherapy ( Galon and Bruni, 2019 ).…”

Comprehensive Analysis of a Ferroptosis-Related lncRNA Signature for Predicting Prognosis and Immune Landscape in Osteosarcoma

“…Tumor development is implicated in the heterogeneity of the TME, such as infiltrating immune cells, extracellular matrix, tumor purity, and non-cellular components ( 65 ). Therefore, we explored the role of the FRL-score in predicting the immune microenvironment landscape of osteosarcoma.…”

A Risk Signature Established From Three Coagulation-fibrinolysis Genes Predicts Prognosis in Digestive System Pancancer

“…There is convincing evidence [13] that m 6 A occurring on mRNA plays an indispensable role in the function of immune cells and innate immune response in the tumor microenvironment. First, we analyzed the correlation of 51 genes [21] encoding immunomodulatory molecules with risk scores and found that these genes were highly expressed in most of the high-risk patients.…”

“…M 6 A methylation modi cation is a dynamically reversible modi cation process that is mainly regulated by m 6 A methyltransferase complexes (writers) such as METTL3, m 6 A demethylases (erasers) such as ALKBH5, and m 6 A binding proteins (readers) such as YTHDC1 [11]. Recently, it has been shown that m 6 A plays an important role in the tumor immune microenvironment (TIME), providing new ideas for clinical immunotherapy [12,13]. However, the m 6 A level and TIME in digestive system pancancer patients with a high incidence of venous thrombosis remain ambiguous.…”