Unraveling the Clinical Landscape of RNA Modification Regulators with Multi-Omics Insights in Pan-Cancer

<b>Background/Objectives:</b> Cancer remains a major global health challenge, with RNA modifications increasingly recognized as key regulators of tumor progression. However, integrated pan-cancer analyses across multiple modification types are limited. <b>Methods:</b> We performed a comprehensive analysis of 170 RNA modification-related genes across 33 cancer types, uncovering diverse expression, mutation, and epigenetic patterns. <b>Results:</b> Key regulators such as <i>IGF2BP3</i>, <i>CFI</i>, and <i>ELF3</i> showed cancer-specific prognostic significance. We developed an RNA Modification Score (RMS) with strong prognostic performance (AUC up to 0.92), correlating with the tumor stage, immune infiltration, and immunotherapy response. High-risk groups exhibited immune checkpoint dysregulation and enriched M1 macrophages in glioblastoma. Drug screening highlighted oncrasin-72 as a potential therapy. Validation via single-cell/spatial transcriptomics and immunohistochemistry confirmed the spatial localization of critical genes like <i>CFI</i> and <i>ELF3</i>. <b>Conclusions:</b> Our study reveals the multifaceted role of RNA modifications in cancer, providing a translational framework for personalized prognosis and therapy in precision oncology.