Establishing a Unified Taxonomy for the Circulating Tumor Microenvironment (cTME) and Circulating Tumor-Associated Cells (C-TACs): A Roadmap for Precision Oncology

Background: The transformative potential of liquid biopsy in precision oncology is currently limited by a critical structural challenge: nomenclature inconsistency. Historically, the term "TME" was employed to denote Tumor Microemboli—multicellular clusters of circulating tumor cells (CTCs) that drive high-efficiency metastasis. In contemporary cancer biology, however, "TME" has transitioned into the universal shorthand for the Tumor Microenvironment, representing the complex systemic ecosystem of malignant and non-malignant components. Objective: This dual usage has led to conceptual ambiguity, where the same term describes both a physical cellular aggregate and a biological landscape, hindering the standard reporting of clinical results. This review seeks to resolve this inconsistency by proposing a rigorous taxonomic framework to decouple these entities and highlight their clinical utility in therapeutic decision-making. Proposed Taxonomy: We advocate for the adoption of Circulating Tumor Microenvironment (cTME) as the inclusive term for the systemic environment, encompassing non-cellular factors such as ctDNA, extracellular vesicles, and biophysical attributes. Conversely, physical cellular clusters should be strictly classified as Circulating Tumor Emboli (CTE). Crucially, we define Circulating Tumor-Associated Cells (C-TACs) as the functional cellular subset within the cTME, encompassing single CTCs, CTE, and supporting non-malignant cells like CTECs and CAFs. Clinical Applications: Establishing this distinction allows for the seamless integration of molecular profiling (NGS) and functional assays. We highlight evidence that C-TACs serve as the primary substrate for Chemo-Response Profiling (CRP), demonstrating high concordance with clinical outcomes. Furthermore, identifying these functional units, particularly perioperative CTE, acts as a critical predictor for the efficacy of adjuvant chemotherapy in early-stage malignancies. Conclusion: Adopting this unified taxonomy is essential for advancing precision oncology. By recognizing the cTME as the superordinate ecosystem and C-TACs as its functional executors, clinicians can more accurately interpret multi-modal liquid biopsy data, transforming these technologies into actionable platforms for personalized real-time cancer management.