RNA Modifications: From Disease Mechanisms to Precision Medicine and Tumor Microenvironment

RNA Modifications: From Disease Mechanisms to Precision Medicine and Tumor Microenvironment

RNA modifications—such as m6A, m5C, ac4C, and Ψ—dynamically regulate gene expression programs, serving as a nexus connecting disease pathogenesis, tumor microenvironment (TME) remodeling, and precision medicine. Their multidimensional regulatory networks in cancer and other complex diseases offer novel insights into pathological mechanisms, targeted drug development, and clinical strategies. Below is a detailed analysis from three perspectives: molecular mechanisms, precision medicine applications, and TME regulation.

I. Disease Mechanisms: RNA Modifications Drive Oncogenic Networks

1. Epitranscriptomic Remodeling of Oncogenic Pathways
   • m6A in Cancer Progression: METTL3, an m6A methyltransferase, catalyzes m6A modifications on oncogenic mRNAs (e.g., MYC, EGFR), enhancing their translation efficiency to promote proliferation and metastasis in lung and colorectal cancers. In hepatocellular carcinoma, the m6A reader YTHDF1 activates PI3K/AKT and MAPK pathways by recognizing m6A-modified FGF9 mRNA, driving angiogenesis and invasion.
   • m5C and Tumor Heterogeneity: NSUN2, an m5C methyltransferase, alters ribosomal function and codon preferences through rRNA and tRNA modifications, facilitating metabolic reprogramming and chemoresistance in cancer cells.
   • ac4C-Mediated Immune Evasion: NAT10-mediated ac4C modifications stabilize PD-L1 mRNA, boosting immune checkpoint protein expression and suppressing T-cell activity.
2. Cross-Regulation of Metabolism and Epigenetics
   • Metabolic Reprogramming: m6A modifications regulate glycolytic genes (e.g., HK2, LDHA) to enhance the Warburg effect. In glioblastoma, FTO (an m6A eraser) upregulates HK2 expression by removing m6A marks, driving lactate accumulation.
   • Chromatin-RNA Crosstalk: METTL3-mediated m6A modifications directly modulate chromatin accessibility (e.g., H3K4me3-marked regions), activating oncogene transcription (e.g., SOX2), challenging the traditional “post-transcriptional regulation” paradigm.
3. Immune Microenvironment Regulation
   • Immunosuppressive Cell Infiltration: Dysregulated m6A in tumor-associated macrophages (TAMs) promotes M2 polarization via IL-6/STAT3 signaling, fostering an immunosuppressive TME.
   • T-Cell Exhaustion: METTL3 deficiency in CD8+ T cells accelerates IFN-γ mRNA degradation, impairing antitumor immunity.

II. Precision Medicine: From Biomarkers to Targeted Therapies

1. Diagnostic and Prognostic Tools
   • Circulating RNA Modification Biomarkers: m6A-modified circRNAs (e.g., circNSUN2) in blood correlate with tumor burden and serve as early diagnostic markers for colorectal cancer.
   • Single-Cell Epitranscriptomics: Single-cell m6A-seq resolves intratumoral heterogeneity, predicting immunotherapy responses (e.g., YTHDF2-high liver cancer patients show better PD-1 inhibitor sensitivity).
2. Targeting RNA Modification Enzymes
   • Small-Molecule Inhibitors:

• METTL3 Inhibitors: STM2457 blocks METTL3’s SAM-binding domain, suppressing acute myeloid leukemia proliferation.
• FTO Inhibitors: MO-I-500 reverses glioma stemness and radiation resistance by inhibiting FTO demethylase activity.
  • RNA Modification-Directed Tools:
• CRISPR-Cas13 Systems: Guide RNAs targeting m6A sites selectively degrade oncogenic mRNAs (e.g., EGFRvIII mutants).
• Aptamer-Drug Conjugates: YTHDF1-targeted aptamers deliver chemotherapeutics specifically to liver tumors.

3. Combination Therapies
   • Immunotherapy Sensitization: METTL3 inhibition enhances tumor antigen presentation (e.g., MHC-I), synergizing with PD-1 inhibitors to prolong survival in melanoma models.
   • Reversing Chemoresistance: Targeting ALKBH5 restores oxaliplatin sensitivity in colorectal cancer by suppressing Wnt/β-catenin signaling.

III. Tumor Microenvironment Regulation: Angiogenesis to Stromal Crosstalk

1. Angiogenesis and Hypoxia Adaptation
   • Pro-Angiogenic Factors: METTL14-mediated m6A modifications stabilize VEGFA mRNA in gastric cancer, promoting endothelial migration and angiogenesis.
   • Hypoxia Response: HIF-1α upregulates FTO to remove m6A marks on pro-apoptotic BNIP3 mRNA, aiding tumor cell survival under hypoxia.
2. Stromal Reprogramming
   • Cancer-Associated Fibroblasts (CAFs): TGF-β from CAFs activates ALKBH5 in tumor cells, destabilizing TIMP3 mRNA via m6A removal to enhance MMP-driven invasion.
   • Exosome-Mediated Transfer: Tumor-derived m6A-modified circRNAs (e.g., circIGF2BP3) activate PI3K/AKT in endothelial cells via exosomes, increasing vascular leakage.
3. Metabolic Competition and Immune Evasion
   • Lactate-Driven Immunosuppression: m6A-regulated LDHA overexpression elevates TME lactate, inhibiting NK cell cytotoxicity.
   • Nutrient Deprivation: NSUN2-mediated m5C modifications boost SLC7A11 translation, helping tumors resist ferroptosis while depleting cystine to impair T-cell proliferation.

IV. Challenges and Future Directions

1. Technical Bottlenecks
   • Dynamic Modification Detection: Current sequencing methods (e.g., m6A-seq) lack single-cell resolution; advanced nanopore sequencing and live-cell imaging are needed.
   • Spatiotemporal Targeting: Light-controlled CRISPR systems may enable precise RNA modification editing in specific cell subsets (e.g., cancer stem cells).
2. Clinical Translation Barriers
   • Tissue-Specific Toxicity: METTL3 inhibitors require tumor-selective delivery (e.g., nanoliposomes with TME-responsive release).
   • Therapeutic Resistance: Tumors may upregulate compensatory enzymes (e.g., FTO upon METTL3 inhibition), necessitating multi-target inhibitors.
3. Emerging Opportunities
   • Multi-Omics Integration: Spatial epitranscriptomics and metabolomics could map RNA modification-metabolite-immune cell interactions in the TME.
   • AI-Driven Drug Design: Deep learning models (e.g., AlphaFold-RNA) may predict RNA-modifying enzyme structures to accelerate drug discovery.

Conclusion

RNA modifications, as core components of the “epitranscriptomic code,” are redefining molecular subtyping and therapeutic paradigms for cancer and complex diseases. From uncovering the METTL3/YTHDF1 axis in immune evasion to developing clinical-stage inhibitors like STM2457, this field bridges basic research and clinical innovation. Future efforts must explore synergistic networks of diverse modifications (e.g., m6A, ac4C, m5C) and establish integrated frameworks—from dynamic modification mapping to clinical translation—to realize the full potential of RNA epigenetics in precision medicine.

Data sourced from public references. For collaboration or domain inquiries, contact: chuanchuan810@gmail.com