m5C methylation modification may be an accomplice in colorectal cancer escaping from anti-tumor effects of innate immunity-type I/III interferon

Abstract

Colorectal cancer (CRC) is one of the most prevalent malignant tumors in the world, and its occurrence and development are closely related to the complex immune regulatory mechanisms. As the first barrier of the body's defense, innate immunity plays a key role in tumor immune surveillance and anti-tumor response, in which type I/III interferon (IFN) is an important mediator with significant antiviral and anti-tumor functions. 5-methylcytosine (m5C) modification of RNA is a key epigenetic regulation that promotes the expression of CRC oncogenes and immune-related genes. It can enhance the proliferation, migration, and invasion of tumor cells by affecting mRNA stability, translation efficiency, and nuclear export. In addition, m5C modification modulates the activity of innate immune signaling pathways and inhibits interferon production and function, further helping tumor cells evade immune surveillance. However, there are insufficient elucidations on the interaction between m5C modification and innate immunity in CRC. In this study, the mechanism of interferon I/III in colorectal cancer was systematically reviewed and explored. This work focused on how m5C modification promotes tumor immune escape by affecting the interferon signaling pathway, thereby providing new diagnostic markers and therapeutic targets for clinical use, and enhancing the immunotherapy efficacy.

Keywords: colorectal cancer; innate immune signaling pathways; m5C methylation; tumor immune escape; type I/III interferon.

Figure 1

The role of m5C modifications in immune signaling regulation. (A) In NSUN2-deficient cells, ncRNAs transcribed by host RNA polymerase (Pol) III, particularly RPPH1 and 7SL RNA, are significantly upregulated, leading to an increase in unshielded 7SL RNA in the cytoplasm. This 7SL RNA acts as a direct ligand for RIG-I-mediated interferon (IFN) responses. In NSUN2-deficient cells, inhibiting Pol III transcription or silencing RPPH1 and 7SL RNA suppresses IFN signaling, partially rescuing viral replication and gene expression. (B) RNA signals through human TLR3, TLR7, and TLR8, but the incorporation of modified nucleosides such as m5C abolishes this activity. Dendritic cells (DCs) exposed to such modified RNA express significantly fewer cytokines and activation markers compared to DCs treated with unmodified RNA. (C) NSUN2 activation maintains global m5C RNA methylation (including TREX2) and stabilizes TREX2 to limit cytoplasmic dsDNA accumulation and cGAS/STING activation, thereby reducing interferon production and promoting tumorigenesis and resistance to anti-PD-L1 immunotherapy. Meanwhile, NSUN5-mediated 5-methylcytosine (m5C) modification of GPX4 sustains redox homeostasis in colorectal cancer (COAD) by activating the cGAS-STING signaling pathway, thereby enhancing anti-tumor immunity.

Figure 2

The role of m5C methylation modification in CRC. (A) m5C modification is catalyzed by methyltransferases that add methyl to cytosine residues of RNA using S-adenosyl-L-methionine (SAM) as a methyl donor. Known m5C methyltransferases include the NSUN family, DNMT2, and TRDMT family. allyref and YBX1 are m5C-binding proteins that regulate mRNA nuclear export as well as RNA stability and translational efficiency, respectively. the TET family (TET1, TET2, and TET3) act as m5C demethylases that remove m5C modifications through Fe (II)-dependent and α-ketoglutarate oxidation to remove m5C modifications. (B) NSUN2 promotes the proliferation and migration of CRC cells by modifying the mRNA of the proto-oncogene SKIL and stabilizing its expression. NSUN2 synergistically modifies the mRNA of the glycolytic enzyme ENO1 with YBX1 to enhance glycolysis and lactate production, forming a positive feedback loop that promotes tumor progression. In addition, NSUN2-mediated m5C modification increased the stability of cyclic RNA circ_0102913 and promoted the malignant behavior of CRC cells. NXPH4 is regulated by m5C modification and promotes the malignant features of colorectal cancer by inhibiting the degradation of HIF1A.TNFRSF10A-AS1 is regulated by m5C modification and affects cell proliferation and invasion, which has potential therapeutic value.