Reframing liquid biopsy microRNAs as functional readouts of Tumor–Microenvironment cross-talk

Liquid biopsy-associated microRNAs have been widely investigated as minimally invasive biomarkers for cancer detection, prognosis, and treatment monitoring. However, their clinical translation remains constrained by methodological variability, incomplete biological contextualization, and limited integration with therapeutic decision-making. This review proposes that extracellular microRNAs may be more informatively interpreted not only as passive indicators of tumor burden, but also as dynamic molecular readouts of tumor–microenvironment cross-talk, extracellular matrix remodeling, immune and stromal reprogramming, and pre-metastatic niche conditioning. We discuss how carrier-resolved profiling may refine the interpretation of circulating microRNAs by distinguishing extracellular vesicle-associated, Argonaute/ribonucleoprotein-bound, lipoprotein-associated, and other extracellular RNA fractions. Particular attention is given to competing endogenous RNA networks, microRNA-binding-site stoichiometry, and the mechanobiological regulation of extracellular vesicle release and microRNA cargo by matrix stiffness. We also examine the translational barriers that continue to limit clinical implementation, including pre-analytical variability, hemolysis, platelet contamination, extracellular vesicle purification, normalization bias, and insufficient prospective validation. Finally, we explore how liquid biopsy-derived RNA states could inform RNA-based therapeutics, biomimetic delivery strategies, and context-dependent theranostic approaches aimed at improving tumor-context specificity while reducing off-target toxicity. By integrating carrier identity, tumor ecosystem biology, RNA competition, mechanobiology, and therapeutic context, this review outlines a conceptual framework that may help guide the evolution of microRNA liquid biopsy from static biomarker discovery toward clinically actionable, network-aware precision oncology.