A Unified Taxonomy for the Circulating Tumor Microenvironment (cTME) and Circulating Tumor-Associated Cells (C-TACs):...

The growing complexity of liquid biopsy in precision oncology demands a structured classification framework that can accommodate its expanding multi-omic scope. As the field has matured from early Tumor Microemboli research-focused on multicellular clusters of circulating tumor cells (CTCs) that drive high-efficiency metastasis-to the broader systemic analysis of the "Tumor Microenvironment" (TME) encompassing malignant and non-malignant components, the need for a hierarchical taxonomy has become evident.

To integrate these diverse data streams into a coherent clinical framework, a multi-tiered classification system is needed. This review proposes a foundational roadmap that formally distinguishes the systemic ecosystem from its physical and functional subsets and highlights 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.

Establishing this distinction allows for the seamless integration of molecular profiling (NGS) and functional assays. We highlight emerging evidence that C-TACs may serve as the primary substrate for Chemo-Response Profiling (CRP), with early proof-of-concept studies reporting high concordance with clinical outcomes that still await independent prospective confirmation. Furthermore, preliminary evidence suggests that identifying these functional units, particularly perioperative CTE, may help predict the efficacy of adjuvant chemotherapy in early-stage malignancies, although this remains to be confirmed in prospective studies.

Adopting this unified taxonomy may help advance precision oncology. By recognizing the cTME as the superordinate ecosystem and C-TACs as its functional executors, clinicians may be better positioned to interpret multi-modal liquid biopsy data, providing a conceptual roadmap for integrating these technologies into platforms for personalized cancer management. We emphasize that this framework is intended to be hypothesis-generating and that its clinical applications require prospective validation before routine adoption.