Epitranscriptomic circuits wiring the tumor microenvironment: A pharmacodynamic framework for clinical translation

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Epitranscriptomic RNA modifications are crucial regulators of gene expression, influencing transcript fate.
• In solid tumors, these marks dictate tumor microenvironment (TME) behavior, impacting oncogenic signaling, immune response, and vascularization.
• Dysregulation of epitranscriptomic marks contributes to cancer progression and treatment resistance.

Purpose of the Study:

• To integrate mechanistic insights of epitranscriptomic circuits with clinical observations for improved cancer trial design.
• To map how epitranscriptomic marks, particularly m⁶A, influence key cancer hallmarks and therapeutic responses.
• To propose a pharmacodynamic workflow and practical principles for clinical translation of epitranscriptomic biology.

Main Methods:

• Review and synthesis of existing mechanistic and clinical data on epitranscriptomic regulation in cancer.
• Integration of multi-omics approaches including LC-MS, direct RNA sequencing, spatial profiling, and ctDNA analysis.
• Development of a bench-to-bedside pharmacodynamic workflow for assessing epitranscriptomic interventions.

Main Results:

• Epitranscriptomic circuits, centered on NF-κB, Wnt/β-catenin, and Dll4-NOTCH pathways, significantly shape the TME.
• m⁶A and related marks modulate stemness, angiogenesis, metastasis, and treatment resistance.
• A comprehensive pharmacodynamic workflow and four operating principles for clinical application are proposed.

Conclusions:

• Epitranscriptomic circuits represent a critical regulatory layer in solid tumors with significant therapeutic potential.
• Translating epitranscriptomic discoveries into clinical practice requires integrated mechanistic and pharmacodynamic approaches.
• The proposed framework facilitates the rational design and combination of epitranscriptomic-based cancer therapies.