Non-Coding RNAs: Architects of Tumor Microenvironment and Therapeutic Potential

The tumor microenvironment (TME) is a dynamic ecosystem in which cancer cells, stromal cells, immune cells, blood vessels, and extracellular matrix interact continuously. This crosstalk shapes tumor growth, metastasis, immune evasion, and resistance to therapy. Non-coding RNAs (ncRNAs) — including microRNAs, long non-coding RNAs, and circular RNAs — have emerged as central regulators of this ecosystem. Beyond controlling gene expression inside tumor cells, ncRNAs act as messengers of intercellular communication, frequently packaged into extracellular vesicles, to reprogram neighboring stromal and immune populations. Deciphering how these RNA molecules are produced, structured, and how they interact with DNA, RNA, and proteins is essential to explain how tumors build and remodel their surroundings. It also opens a distinct therapeutic space in which RNA can be targeted, mimicked, or delivered as a precision anticancer strategy.This Research Topic distinguishes itself by requiring mechanistic depth over descriptive correlation. Rather than cataloguing which ncRNAs are dysregulated in the TME, we aim to resolve how a given ncRNA acts — its biogenesis, structure, and direct molecular interactions with DNA, RNA, or protein partners — and to demand that every proposed mechanism be substantiated through functional validation. We specifically prioritize studies combining CRISPR-Cas9-based genetic perturbation with advanced bioinformatics for RNA interaction and network analysis, ensuring that computational predictions of ncRNA function are experimentally confirmed. This dual-evidence standard is intended to yield mechanistically robust, reproducible findings that move the field beyond correlative profiling toward causally validated ncRNA targets for cancer therapy.We welcome Original Research, Reviews, Mini-Reviews, Methods, and Perspective articles addressing, but not limited to:• Functional dissection of ncRNA-driven regulation of stromal cells (cancer-associated fibroblasts, endothelial cells) confirmed through CRISPR-Cas9 gene editing or loss-/gain-of-function validation• ncRNA control of immune cell recruitment, polarization, and exhaustion, and immunotherapy response/resistance, with mechanism confirmed by targeted genetic perturbation• Extracellular RNA communication and vesicle-mediated ncRNA transfer, mapped through bioinformatics-driven RNA interaction and network analysis with experimental corroboration• ncRNA regulatory networks (ceRNA, RNA–protein complexes) in TME remodeling, validated by integrating computational prediction with wet-lab confirmation• RNA modifications and epigenetic mechanisms shaping the TME, identified via sequencing-based bioinformatics and mechanistically verified• ncRNA structure–function relationships informing RNA-targeted diagnostics/therapeutics, supported by CRISPR-based functional proof• Single-cell, spatial transcriptomic, and multiomic approaches to decipher ncRNA-tumor microenvironment dynamics, with mechanistic validation through functional studies.Please note: studies combining public database mining with subsequent in vitro/in vivo or independent-cohort validation are welcome; manuscripts consisting solely of bioinformatics or computational analysis of public genomic/transcriptomic databases, without such validation, are outside the scope of this Research Topic and will not be accepted. Topic editors: Chun Ju Chang, Nicoletta Potenza Source: https://www.frontiersin.org/research-topics/83873/non-coding-rnas-architects-of-tumor-microenvironment-and-therapeutic-potential